The OBR Blog

January 20, 2017 - 05:01 pm Posted in ASCO GI comments0 Comments

By Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

Before Cyramza® (ramucirumab, Eli Lilly and Co) was approved by the U.S. Food and Drug Administration (FDA) in 2014, no targeted therapy regimens were approved for use in relapsed/refractory gastric cancer. Cyramza’s approval as a monotherapy or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing systemic therapy was based on the positive results of two Phase III studies in relapsed gastric patients: the REGARD trial, which showed a significant overall survival (OS) benefit of 5.2 months for Cyramza versus 3.8 months for placebo,1 and the RAINBOW trial, which compared Cyramza plus paclitaxel versus paclitaxel alone, demonstrating a significant progression free survival (PFS) and OS benefit for the Cyramza combination (OS: 9.63 months in Cyramza plus paclitaxel arm versus 7.36 months in paclitaxel alone arm).2 Cyramza had a significant first-to-market advantage in this indication and is currently highly utilized in this space (30.4% as monotherapy or with paclitaxel in second-line in the U.S.).3 However, given the limited number of treatment options, new agents still have a lot of potential, including immunotherapies, which have already made a splash in other solid tumor types.

While gastric cancer is a relatively rare tumor type in the United States (ranks 16th in terms of incidence), it is the most commonly diagnosed tumor type in Japan.3 In part due to this, Ono Pharmaceuticals took the lead in evaluating immunotherapy in gastric cancer in Asia Pacific. In 2014, Ono Pharmaceuticals (which is co-developing Opdivo along with Bristol-Myers Squibb) initiated a randomized (2:1), double-blind, Phase III trial of Opdivo® (nivolumab) in gastric and gastroesophageal junction (GEJ) cancer patients in Japan, Korea and Taiwan (ONO-4538-12; NCT02267343).  In this trial, Opdivo (3 mg/kg q2w) was compared against placebo in patients refractory or intolerant to standard therapies. The primary endpoint was OS. In yesterday’s oral abstract session at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, positive data from this trial were presented.4 The trial enrolled 493 patients with unresectable advanced or recurrent gastric/GEJ cancer who had failed two or more previous chemotherapy regimens, including Cyramza. As of the data cut-off on August 13, 2016, 5.6 months after the last patient was randomized, median OS was 5.32 months with Opdivo versus 4.14 months with placebo (hazard ratio, 0.63; 95% confidence interval (CI), 0.50-0.78; p<0.0001), and OS rates at six and 12 months were 46.4% versus 34.7% and 26.6% versus 10.9%, respectively. The overall response rate was 11.2% with Opdivo versus 0% with placebo (p<0.0001). Median PFS was 1.61 months with Opdivo versus 1.45 months with placebo (HR, 0.60; 95% CI, 0.49-0.75; p<0.0001). Grade ≥ 3 drug-related adverse events (AEs) occurred in 11.5% of Opdivo-treated patients and in 5.5% of placebo-treated patients; 2.7% and 2.5% of patients, in the respective arms, discontinued study treatment due to drug-related AEs (any grade). The most common AEs were pruritus, diarrhea, rash, fatigue, and decreased appetite. These data were well received by the conference audience. Of particular excitement was the characteristic OS plateau or “tail” in the Kaplan-Meier curve that we have come to expect from the checkpoint inhibitor class of immunotherapy agents; while the OS difference at the median was modest (1.18 months), a strong separation between the two curves that appears to be maintained long-term. Biomarker analysis was not reported, but is ongoing.

Not surprisingly, Ono has already filed for approval of Opdivo in gastric cancer in Japan with this data. Despite the Japanese filing, BMS has not stated that it has plans to file in the U.S. based on this data, perhaps given the enrollment was limited to Asian populations. Indeed during the discussion, Dr. Lenz of USC Norris Comprehensive Cancer Center took care to point out the molecular differences in gastric cancer between Asian and non-Asian populations citing reported differences in immune signatures.5  Furthermore, subgroup analysis in this trial showed a stronger magnitude of benefit (HR 0.59) in patients with intestinal histologic type (a better prognostic subset that is more common in Asian gastric cancer patients) compared with patients with diffuse histology type (HR 0.82; a worse prognostic subset that is more common in Caucasian gastric cancer patients). Together, this information raise doubts about the translatability of these data in Asian patients to a broader U.S. population. During the question-and-answer portion, however, the issue of U.S. filing based on these Asian data was raised, and some felt that, rather than wait for a new Phase III trial readout, a confirmatory Phase II trial in a U.S. population could warrant filing. Although not raised in yesterday’s session, an alternative scenario could be the National Comprehensive Cancer Network (NCCN) recommending Opdivo for use in relapsed/refractory gastric/GEJ. Such action (NCCN guideline recommendation for U.S. patients based strictly on Asian data) has not previously occurred but might not be entirely outside the realm of possibility given the unmet needs in gastric cancer and the well-established safety profile for Opdivo in other indications, even if balanced against the histologic subgroup data from the Japanese trial. In the absence of accelerated filing or NCCN recommendation, filing with the FDA may need to await the results of the ongoing global Phase III CheckMate 649 trial (NCT02872116) that is being conducted in the first-line setting and is investigating the combination of Opdivo plus Yervoy® (ipilimumab, BMS/Ono), data from which is not expected for several years.

Opdivo is not the only immunotherapy under late-stage development in gastric cancer. Keytruda® (pembrolizumab, MSD) has multiple Phase III trials underway in first-line and relapsed/refractory disease and may be the first immunotherapy agent to enter the gastric cancer market in the United States. Pfizer and Merck KGaA are also developing their PD-L1 inhibitor avelumab in relapsed/refractory gastric cancer.  And of course non-immunotherapy approaches are also under late-stage development, including napabucasin (BBI608, Boston Biomedical/Sumitomo Dainippon) in second-line (NCT02178956), Lonsurf® (trifluorothymidine/tipiracil hydrochloride, Taiho) in third-line, GS-5745 (Gilead) in first-line, and Cyramza in first-line.  Although the results of this Asian Phase III trial may not have an immediate impact in the U.S. gastric cancer market, these remain highly impactful results globally. Opdivo could gain approval in this indication in Japan as early as late 2017, putting it well-ahead of other competitors in this setting and bringing a new option to this population of high unmet need.

References

  1. Fuchs CS, et al.; “Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, Phase 3 trial;” Lancet, 383 (9911): 31-39, 2014.
  2. Wilke H, Muro K, Van Cutsem E, et al.; “Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial;” Lancet Oncol, 15 (11): 1224-1235, 2014.
  3. Kantar Health, CancerMPact Treatment Architecture and Patient Metrics, accessed January 20, 2017. Available at www.cancermpact.com.
  4. Kang et al;. “Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial.” J Clin Oncol 35, 2017 (suppl 4S; abstract 2).
  5. Lin SJ, et al.;” Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas.” Gut. Nov;64(11):1721-31 2015.

January 18, 2017 - 01:01 pm Posted in ASCO GI comments0 Comments

Three presentations to be featured at the 2017 Gastrointestinal Cancers Symposium were singled out as newsworthy at a pre-meeting presscast. The presentations focused on:

  • Use of PET scans after induction chemotherapy to guide further treatment for esophageal cancer
  • A watch-and-wait approach that can avoid surgery in some patients with rectal cancer, and
  • The life-prolonging effects of physical activity for patients with advanced colorectal cancer

PET Scan Guidance (Abstract 1)

Use of PET scans to assess response to induction chemotherapy may allow tailoring of subsequent chemotherapy, vastly improving outcomes for patients with esophageal cancer, according to results of a phase II trial.

“PET scans may prove to be a valuable tool to help oncologists fine-tune the use of chemotherapy for esophageal cancer and maximize the benefits of chemotherapy for each individual patient,” said ASCO Expert Nancy Baxter, MD, moderator of the presscast. “This is heartening evidence for a new approach to treating a disease where innovation is sorely needed.”

Standard treatment for stage II-III esophageal and gastroesophageal junction (GEJ) cancers consists of 5.5 weeks of chemoradiation followed by surgery. Thus far, there is no way to predict which of several chemotherapy regimens will be most effective for an individual patient. The present study utilized PET imaging in 257 patients with stage II-III esophageal and GEJ cancers who were randomized to one of two induction chemotherapy regimens (modified FOLFOX-6 or carboplatin/paclitaxel).

After an initial PET scan at baseline, a second PET scan was obtained following the first few cycles of induction chemotherapy. If the PET scan suggested the regimen was effective, patients continued the same regimen during chemoradiation. If the PET scan suggested that the regimen was not effective, chemotherapy was switched to the other regimen during chemoradiation. Based on PET scan results, switching occurred in 29/129 patients randomized to FOLFOX-6 and 49/128 randomized to carboplatin/paclitaxel.

This study found that PET used to guide therapy after induction chemotherapy achieved improved pathological complete response (pCR) — a surrogate marker for survival in esophageal cancer after induction chemotherapy — compared with previous studies that did not utilize the PET-guided approach.

The pCR rate for non-responding patients was 19% for those who switched to carboplatin/paclitaxel and 17% for those who switched to FOLFOX-6. The pCR rate for all PET non-responding patients taken together was 18%. These pCR rates compare favorably with a 5% pCR rate previously reported in PET nonresponders to induction chemotherapy.

For PET responders, pCR was 26%, and for all patients on study, pCR was 23%.

This is one of the first studies to show the benefit of PET imaging in informing pre-surgery treatment decisions for this type of cancer.

“This strategy [using PET after induction chemotherapy to assess response] can be used in clinical trials to identify the most effective chemotherapy regimens,” said lead author Karyn A. Goodman, MD, University of Colorado School of Medicine, Aurora, CO.

Watch-and-Wait Approach for Rectal Cancer (Abstract 521)

It is possible for strictly selected patients with stage II-IV rectal cancer — that is, patients with no evidence of residual cancer following induction therapy — to forego surgery, according to a large, observational, “real world” study. Using a “watch-and-wait” approach following initial treatment with chemotherapy and/or radiation did not compromise 3-year survival rates.

“Some people with rectal cancer undergo surgery after chemoradiation therapy, even though it may not be necessary,” said study co-author Maxime van der Valk, MD, International Watch and Wait Database (IWWD) Consortium, Leiden University Medical Center, Leiden, the Netherlands. “From the data we have now, it seems that a watch-and-wait may be safe in selected patients with rectal cancer, but it is too soon to say whether this approach should be routinely offered.”

The study was based on an analysis of 679 patients of a total of 802 patients enrolled in the IWWD database (35 institutions from 11 countries). All patients had no signs of residual cancer after induction treatment, as assessed by physical exam, endoscopy, or MRI/CT scans following chemotherapy and radiation. All patients were managed by watch-and-wait care, which included extensive monitoring for recurrence every 3 months by endoscopy, MRI scan, and physical exam for the first 2 years.

At a median follow-up of 2.6 years, 25% of patients underwent delayed surgery due to local recurrence, and distant metastasis was reported in 7%. The 3-year survival rate was 92% among all patients and 87% among those who had a recurrence. These data are comparable with historic data from patients who undergo surgery.

This is not a practice-changing trial, and “watch and wait” is not yet included in treatment guidelines, but it does tell us more about which patients should be considered for this strategy, Dr. van der Walk said.

Dr. Baxter, session moderator, said: “Five years ago, it would have been considered heresy to treat rectal cancer without surgery. Over the past few years, we are beginning to consider this but there are no standard protocols or guidelines. It is an evolving area and patient selection will be critical.”

Physical Activity Associated with Improved Survival in Advanced CRC (Abstract 659)

Even though it may be difficult to exercise with advanced colorectal cancer (CRC), moderate physical activity appears to be life-extending, according to a smaller trial embedded in a large phase III trial of 1,231 patients designed to evaluate chemotherapy for metastatic CRC.

Prior to starting chemotherapy, patients reported their physical activity level on a questionnaire. The researchers determined the level of physical activity per week for each patient. Patients who were engaged in 30 or more minutes each day of moderate physical activity (i.e., walking, cleaning, or gardening) had a 19% reduction in mortality and a 16% reduction in disease progression compared with those who spent the least amount of time engaging in moderate physical activity (i.e., 30 minutes of moderate physical activity per week).

Engaging in the physical activity also was linked to improved survival; patients who walked 4 or more hours per week had a greater than 20% improvement in overall survival, and those who participated in 5 or more hours a week of nonvigorous physical activity (i.e. yoga or walking) had a 25% improvement in overall survival.

“These findings suggest that as little as 30 minutes a day of moderate physical activity may improve outcomes,” said lead author Brendan John Guercio, MD, resident at Brigham & Women’s Hospital in Boston, MA. “While exercise is by no means a substitute for chemotherapy, patients can experience a wide range of benefits from as little as 30 minutes of exercise a day.”

No association was found between vigorous physical activity and cancer outcomes, but the numbers of patients engaging in vigorous physical activity were too small to show statistical significance.

This is one of the first studies to show a link between level of physical activity in patients with CRC and distant metastases. Prospective studies are needed to confirm these associations.

The 2017 Gastrointestinal Cancers Symposium is jointly sponsored by the American Gastroenterological Association (AGA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SGO) and will take place January 19-21, 2017, at the Moscone Convention Center in San Francisco.

by John McCleery

January 17, 2017 - 07:01 pm Posted in ASH Conference Coverage comments0 Comments

By Lynne Lederman, PhD

At this past December’s American Society of Hematology (ASH) annual meeting, the late-breaking abstract (LBA) session was devoted to presentations selected by the Program Committee for featuring substantive, novel, and groundbreaking data that were not available by the general abstract submission deadline and would not otherwise have been presented at the meeting.

The presentation on phase 2 results of the ZUMA-1 trial of the chimeric antigen receptor (CAR) therapy KTE-C19 (axicabtagene ciloleucel) in patients with chemotherapy-refractory diffuse large B-cell lymphoma1 has attracted a lot of attention.2

Here we report on 4 other presentations in the LBA session that are also likely to affect the outcome of patients with cancer in the future.

Adding Consolidation or Second Transplant to Single Transplant and Maintenance Does Not Improve Outcomes in Multiple Myeloma

Edward A. Stadtmauer, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, presented primary results from the randomized, prospective phase 3 trials of the Bone and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 STaMINA trial (NCT01109004).3

This trial investigated whether the addition of a second autologous hematopoietic stem cell transplant (AHCT) or consolidation therapy combining a proteasome inhibitor (PI) with an immunomodulatory agent (IMiD) to upfront treatment of multiple myeloma (MM) with AHCT plus lenalidomide maintenance would provide additional benefit.

The study enrolled transplant-eligible patients with symptomatic MM who were age £70 years within 2 to 12 months of initiating ³2 cycles of systemic therapy, without prior disease progression, who had sufficient autologous stem cells available. Patients (N=758) were randomly assigned to receive:

  • Melphalan 200 mg/m2 AHCT and 4 cycles of consolidation therapy (lenalidomide 15 mg daily on days 1 to 14; dexamethasone 40 mg days 1, 8, and 15; and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle) (ACM) (n=254) OR
  • Tandem melphalan 200 mg/m2 AHCT (n=247) OR
  • A single AHCT (n=257)

All patients also received maintenance therapy with lenalidomide, initially at 10 mg/day for 3 cycles, then 5 to 15 mg/day for 3 years as tolerated. In 2014 an amendment to the protocol allowed maintenance therapy to continue for an indefinite duration until disease progression.

The primary objective was to compare 38-month progression-free survival (PFS) of patients in the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. The 38-month period allowed 2 months to obtain the first transplant plus 3 years of follow-up.

Secondary endpoints in all 3 arms included overall survival (OS); response rates; rate of conversion to complete response (CR) for patients who did not have CR; toxicity, including infections, after each intervention and long-term toxicity; rate of non-compliance with protocol therapy; treatment-related mortality; and quality of life (QoL).

Enrollment was completed ahead of the projected time. Patients were stratified by risk, with high-risk MM defined by high beta-2 microglobulin and high risk cytogenetic abnormalities. Demographics were balanced across the groups. Over 90% of patients had either a proteasome inhibitor (PI) or immunomodulatory drug (IMiD) as initial therapy, and over 50% had both. The median follow-up time for myeloma status was 37.8 months.

The second AHCT was not administered to 32.0% in the tandem AHCT arm; 11.8% of patients in the AHCT/consolidation arm did not receive consolidation. Maintenance therapy was not started in 16.6% and 16.9% of patients in these arms, respectively, whereas only 5.4% of patients in the single AHCT arm did not receive maintenance.

There was no difference in the primary endpoint, PFS, among arms, with a 38-month estimate of PFS of 56.5 months in the tandem transplant arm, 56.7 months in the transplant/consolidation arm, and 52.2 months in the single transplant arm. Likewise, there was no significant difference in OS among the groups (82.0, 85.7, and 83.4 months, respectively), or in PFS or OS for patients with either standard-risk or high-risk MM.

Treatment-related mortality was low: 4 deaths in the tandem group, 3 in the consolidation group, and 1 in the single transplant group. Secondary primary malignancies were reported in all arms (5.1% in the total population; 14, 15, and 10, incidents respectively),

This trial is the largest randomized comparison of post-transplant approaches for MM in the United States. It shows that after initial therapy with PIs and IMiDs, an initial AHCT, and prolonged lenalidomide maintenance therapy, the addition of consolidation therapy with bortezomib, lenalidomide, and dexamethasone after transplant or use of a second transplant do not produce incremental PFS benefits.

These results also show that induction triplet therapy containing a PI and IMiD followed by a single transplant is sufficient, and may spare patients the additional burden of a second transplant or consolidation.

Companion protocols to this trial include BMT CTN 07LT, which continues long-term follow-up and maintenance therapy to patients in the original trials who completed 3 years of maintenance therapy without disease progression. An analysis including PFS, OS, second primary malignancies, event-free survival, and quality of life (QoL) will be conducted when all surviving patients are >5 years post-randomization, which is expected around 2018.

The PRiMER protocol adds a minimal residual disease (MRD) assessment by flow, and correlative analyses of bone marrow and blood samples to be conducted in 2017. MRD assessment by gene sequencing is on-going.

Newly Identified Mutations Increase Risk for Hereditary ALL

Inherited mutations in the gene IKZF1 are associated with increased risk of developing childhood acute lymphocytic anemia (ALL), the most common childhood cancer, and a leading cause of cancer-related death in children. Both common and rare germline variants have been previously reported to be associated with inherited risk of childhood ALL.

Michelle L. Churchman, PhD, St. Jude Children’s Research Hospital, Memphis, Tennessee, reported on identification of a germline mutation in the IKZF1 gene that is associated with multiple cases of childhood ALL in a single famliy.4

The IKZF1 gene encodes the protein Ikaros, a member of the family of zinc finger transcription factors, which plays a role in lymphocyte development. Analysis of members of this family suggested that an inherited mutation in IKZF1 was associated with ALL.

The aims of this project were to determine the prevalence of inherited IKZF1 variants in ALL, and to determine if germline variants affect the function of IKZF1.

Germline DNA from 4,957 patients with sporadic ALL enrolled in frontline trials of St. Jude Children’s Research Hospital and the Children’s Oncology Group was subjected to targeted IKZF1 next-generation sequencing.

Common variants, non-coding, and synonymous variants were excluded; 44 patients were found to have germline IKZF1 mutations, of which 27 were unique variants.

These unique variants were shown to de-repress transcriptional targets, deregulate adhesion molecule expression leading to aberrant cell-stroma adhesion in the bone marrow in vivo, and conferred reduced response to treatment with dexamethasone and dasatinib in vitro and in vivo.

The results identify IKZF1 as a new ALL predisposition gene, and that germline variants play a role in the pathogenesis of ALL and response to therapy. An important question to answer is whether or not germline IKZF1 variants can be used to predict prognosis in ALL.

Ibrutinib Resolves Steroid-Resistant GVHD

Chronic graft-versus-host disease (cGVHD) is the most common cause of morbidity in patients who have received an allogeneic stem cell transplant. There are no approved treatments for cGVHD that is unresponsive to corticosteroids. David Miklos, MD, Stanford University, Stanford, California, presented the results of a multicenter, open-label, phase 2 study of ibrutinib in patients whose cGVHD failed to respond to corticosteroids and were in need of further treatment (PCYC-1129; NCT02195869).5

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) that also inhibits interleukin-2 (IL-2)-inducible T-cell kinase (ITK), and has been approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), including CLL/SLL with 17p deletion, Waldentrom’s macroglobulinemia, and mantle cell lymphoma that has been treated with at least 1 prior therapy.6

Ibrutinib had been shown to reduce the severity of cGVHD in preclinical models and early clinical studies. Early results from the study supported the designation of ibrutinib as breakthrough therapy for cGVHD after failure of one or more lines of systemic therapy.7

The study enrolled patients with cGVHD that had failed £3 prior lines of therapy who had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4.

Ibrutinib was given orally at 420 mg until progression of cGVHD or unacceptable toxicity. The primary endpoint was response per the 2005 NIH consensus response criteria. Secondary endpoints included rate of sustained response, change in symptoms and corticosteroid requirements, and safety. Additional exploratory endpoints included effects on lymphoid and myeloid signaling pathways and plasma cytokines and chemokines.

The 42 enrolled patients had myeloablative (43%) or non-myeloablative (57%) transplants from related (40%) or non-related (60%) donors. Most had matched peripheral stem cells. Indications included acute and chronic anemias and other hematologic malignancies. All had prior corticosteroid, with a median of 2 prior regimens.

At a median follow-up of 14 months, 29% of patients were still taking ibrutinib; adverse events were the most frequent cause of discontinuation (33%).

Adverse events (AEs) were consistent with those reported for B cell malignancies treated with ibrutinib and those observed in patients with cGVHD treated with corticosteroids, and included fatigue, diarrhea, muscle spasms, nausea, and bruising.

Serious AEs occurred in 52% of patients including pneumonia, septic shock, and fever; 2 deaths due to multilobular pneumonia and bronchopulmonary aspergillosis occurred. Dr. Miklos commented that the lack of cardiac complications might be attributed to the small patient population.

A complete response (CR) (defined as complete resolution of all reversible manifestations of cGVHD) was observed in 9 patients; the overall response rate was 67% (CR plus partial response); 71% of the 28 patients with complete or partial responses had a sustained response for at least 5 months.

Responses were observed across multiple affected organs including skin, mouth, liver, and gastrointestinal tract, and patients with multiple organ involvement generally had responses in 2 or more organs. Overall, 62% (n=26) of patients had corticosteroid doses of <0.15 mg/kg daily, representing a reduction in corticosteroid use, during the study, and 5 discontinued all corticosteroids.

Soluble plasma factors related to inflammation, fibrosis, and cGVHD, such as pro-inflammatory cytokines, chemokines, and tissue growth factors, including tumor-necrosis factor alfa, interleukins, and epidermal growth factor, decreased with ibrutinib therapy.

These results support the investigation of ibrutinib for the front-line treatment of cGVHD in a randomized, double-blind study that is on-going.8

Pacritinib Benefits Patients with Myelofibrosis

John Mascarenhas, MD, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, New York, presented the results of the PERSIST-2, open-label, phase 3 study, which compared the safety and efficacy of pacritinib (200 mg twice daily or 400 mg once daily) to currently available therapies, including ruxolitinib, in patients with myelofibrosis who had platelet counts of £100,00 per microliter.

Ruxolitinib is a Janus kinase (JAK1/2) inhibitor, approved by the FDA in 2011 to treat intermediate- or high-risk myelofibrosis, which is a life-threatening condition. Ruxolitinib reduces splenomegaly and myelofibrosis symptoms, but causes dose-limiting cytopenias, and is not indicated for those with platelet counts <50,000 per microliter.10 Therefore, individuals with myelofibrosis and severe thrombocytopenia represent a population with unmet needs.

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, and other enzymes, and reduced spleen volume and controlled symptoms of myelofibrosis compared with best available therapy (BAT excluding JAK2 inhibitors) regardless of platelet count.

Pacritinib was placed on full clinical hold by the FDA on February 8, 2016 due to concerns about interim survival results, bleeding, and cardiovascular events. The trial was shortened due to the clinical hold.11 However, the hold was recently lifted, and a new trial is set to begin that is enrolling as many as 105 participants with primary myelofibrosis who have failed previous ruxolitinib therapy.12

Of patients enrolled in the pacritinib once daily (n=104), pacritinib twice daily (n=107) or BAT (n=100) groups, nearly all discontinued treatment, mostly due to the clinical hold.

Analyses were done at week 24 prior to the hold. Half the patients in the BAT had crossed over to pacritinib treatment. BAT had consisted of ruxolitinib (45%), hydroxyurea (19%), or “watch and wait” (19%).

Pacritinib was associated with statistically significant reduction in spleen volume vs BAT (P=.001 vs pacritinib groups combined, P=.017 vs once daily, P=.001 vs twice daily).

The twice daily dose of pacritinib was associated with significant ≥50% reduction in total symptom score vs BAT, whereas the once daily dose was not. This may be due to higher steady-state plasma levels associated with the twice daily dose.

Platelet count in patients with a baseline platelet count of <50,000 per microliter increased in both pacritinib groups, and to a greater extent in the once daily group.

Patients treated with pacritinib also had lower requirements for red blood cell transfusion that those in the BAT group at weeks 12 and 24. OS for the pacritinib groups and the BAT group censored at the date of clinical hold were not significantly different.

Pacritinib was associated with more AEs than BAT, primarily diarrhea, nausea, vomiting, anemia, and thrombocytopenia, and were generally less frequent with twice daily dosing. Deaths due to AEs and/or progressive disease occurred in all groups at about the same rate.

In the discussion that followed his presentation, Dr. Mascarenhas said pacritinib was well tolerated and offered symptom relief in a patient population that was quite ill. He continued that his opinion as a clinical investigator is that pacritinib is an effective drug, with a benefit-risk ratio in its favor, and he hopes to see the drug move forward, although additional trials will require FDA approval.

 

References

  1. Neelapu SS, Locke FL, Bartlett NL, et al. Kte-C19 (anti-CD19 CAR T Cells) induces complete remissions in patients with refractory diffuse large B-cell lymphoma (DLBCL): results from the pivotal phase 2 Zuma-1. Blood 2016 128:LBA-6.
  2. Wolfe G, Grisolano J. CARs of the future on display at ASH 2016 as ZUMA-1 wows the crowd. The OBR Blog. http://obroncology.com/blog/.
  3. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with Len maintenance (ACM), tandem autoHCT with Len maintenance (TAM) and autoHCT with Len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). Blood 2016 128:LBA-1.
  4. Churchman ML, Qian M, Zhang R, et al. Germline genetic variation in IKZF1 and predisposition to childhood acute lymphoblastic leukemia. Blood 2016 128:LBA-2.
  5. Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Blood 2016 128:LBA-3.
  6. Imbruvica® (ibrutinib) capsules, for oral use. Prescribing information. Pharmacyclics, LLC, Sunnyvale, California. June, 2016.
  7. Ibrutinib (IMBRUVICA®) Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) for the Development of a Treatment for Chronic Graft-Versus-Host Disease (CGVHD).; 2016. Available at: http://www.prnewswire.com/news-releases/ibrutinib-imbruvica-granted-breakthrough-therapy-designation-by-us-food-and-drug-administration-fda-for-the-development-of-a-treatment-for-chronic-graft-versus-host-disease-cgvhd-300291651.html. Accessed January 9, 2017.
  8. Ibrutinib in Combination with Corticosteroids versus Placebo in Combination with Corticosteroids in Subjects with New Onset Chronic Graft Versus Host Disease (cGVHD) (iNTEGRATE). https://clinicaltrials.gov/ct2/show/NCT02959944. Accessed January 9, 2017.
  9. Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the Persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/µl. Blood 2016 128:LBA-5.
  10. Jakafi® (ruxolitinib) tablets for oral use. Prescribing information. Incyte Corporation, Wilmington, Delaware. March 2016.
  11. Adams B. Struggling CTI reveals new pacritinb data, misses a primary endpoint. August 29, 2016. http://www.fiercebiotech.com/biotech/struggling-cti-reveals-new-pacritinib-data-misses-a-primary-endpoint. Accessed January 5, 2017.
  12. PR Newswire. CTI BioPharma Announces Removal of Full Clinical Hold On Pacritinib. January 5, 2017. http://finance.yahoo.com/news/cti-biopharma-announces-removal-full-063000655.html. Accessed January 9, 2017.

 

January 17, 2017 - 07:01 pm Posted in ASH Conference Coverage comments0 Comments

Introduction

Presenting you with timely market feedback from the 58th ASH Annual Meeting held in December 2016, OBR and MDoutlook® are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report examines US oncologists’ awareness, views and early involvement with the CAR-T cell therapies being developed for a variety of hematologic malignancies.

OncoPoll™ Methodology

  • Primary research phase involved a survey to verified and validated US hematological and medical oncologists with an identified clinical interest in B-cell lymphomas utilizing targeting parameters within the proprietary MDoutlook global cancer treater panel
  • Timing: December 2016. Launched 9 days after close of 2016 American Society of Hematology (ASH) Annual Meeting, held in San Diego, CA, December 3-6, 2016
  • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
  • Data capture via interactive web-based survey instrument, utilizing proven MDoutlook methodology and proprietary technology
  • Multiple formulations / variants of the same target antigen & malignancy combination were often presented but the survey grouped all target antigen + malignancy together. Where relevant, reference was made to multiple abstracts in each category and links to these abstracts on the ASH website were provided within the survey for physician reference
  • Reponses at data collection: 100

Awareness and Expected Impact of Various CAR-T Cell Approaches for B-Lineage Malignancies

Key Conclusions

  • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have an average / slightly above average awareness of these presentations
    • A general higher level of awareness is seen by those who attended ASH
    • The average level awareness about the CD19 directed CAR-T cells in B-cell ALL is somewhat higher than others, as expected, since this approach is the furthest along in clinical development
  • All of these approaches, as rated on a 1 – 5 scale of 1 = not at all important to 5 = very important, are seen as being very clinically meaningful
    • CD19-directed CAR-T cell approach for B-cell ALL is held in a slightly higher regard than the other approaches
    • Attendees of the ASH Annual Meeting consistently rate each of these approaches as more important than the non-attendees, but only by a consistently small margin (0.1-0.4 pts)

Current Impact of CAR-T Studies on Clinical Practices

Key Conclusions

  • When asked about patient referrals to clinical trials for CAR-T cell therapies, meeting attendees average nearly 4 patients over the past year, whereas the non-attendees are around 1.5 patients. When separating respondents based on practice setting (academic vs. community), the averages are mostly similar (averages 2.6-3.0 patients per year)
  • When asking how common it was for patients to already ask about being treated with a CAR-T cell approach, ¾ of the attendees state that they have been asked about it (avg. 8 patients in last 6 months) while ~40% of non-attendees have been asked about it (avg. 2 patients in last 6 months)
    • Taking these 2 questions together, it appears that attendees could be considered “clinical investigators” and their patients tend to know this about them. As such, the patients of meeting attendees are more willing to ask for the newest treatment approaches (self-selection of patients to different physician types)
  • The involvement / leadership of NIH investigators in the CAR-T cell therapy development is seen as a positive aspect by US physicians, consistently rating ~7 on a 10-point scale

Conclusions: CAR-T Cell Therapies for B-Lineage Malignancies

  • All of these studies highlight the importance of the ASH Annual Meeting to the entire hematologic oncology community – awareness of each of these presentations are high and can occur quite quickly even for those who did not attend the meeting. Alternative methods to disseminate new clinical information are very important to improving clinical practices and patient outcomes
  • CAR-T cell therapies are already impacting clinicians in their day-to-day practices, even though they are not yet commercially available. Patients are asking their oncologists about them and physicians are regularly referring patients to their clinical trials.

For a more detailed analysis report, please click here to download the full report.

Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.

January 06, 2017 - 11:01 pm Posted in ASH Conference Coverage Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) comments0 Comments

Introduction

In an effort to provide you with timely market feedback from the 58th ASH Annual Meeting held in December 2016, OBR and MDoutlook® are pleased to share results from MDoutlook’s OncoPolls™ conducted last month immediately after the meeting. This report explores the choice between Rituxan® and Gazyva® in the front line setting for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and the use of Rituxan and Revlimid® in the maintenance setting for mantle cell and CLL, respectively.

OncoPoll™ Methodology

  • Primary research phase involved a survey to verified and validated US hematological and medical oncologists with an identified clinical interest in B-cell lymphomas utilizing targeting parameters within the proprietary MDoutlook global cancer treater panel
  • Timing: December 2016. Launched 9 days after close of 2016 American Society of Hematology (ASH) Annual Meeting, held in San Diego, CA, December 3-6, 2016
  • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
  • Data capture via interactive web-based survey instrument, utilizing proven MDoutlook methodology and proprietary technology
  • Links to discussed abstracts on the ASH website were provided within the survey
  • Reponses at data collection: 100

Institutional Setting by Attendance of Respondents

oncopoll_nhl_attendance

Use of anti-CD20 mAbs in the Front Line for Different B-cell Lymphomas

Awareness of Abstracts #6 & #470

oncopoll_nhl_awareness

 General Clinical Importance of Different anti-CD20 mAbs in FL & DLBCL

oncopoll_nhl_importance

Expected Impact on anti-CD20 Usage in FL & DLBCL

 oncopoll_nhl_impact

Key Conclusions

  • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have only an average / slightly below average awareness of these presentations
    • A general higher level of awareness is seen by those who attended ASH (nearly a full rating point higher for each abstract)
    • The average level awareness about the FL abstract is somewhat lacking considering it was presented in the Plenary Session
  • Clinical impact of these presentations, rated on a 1 – 5 scale of 1 = not at all important to 5 = very important, is seen as being very clinically meaningful
    • US oncologists assign a high importance (>4) to the FL presentation (Abstract #6), regardless of meeting attendance
    • Abstract #470 (concerning DLBCL) is seen as somewhat less important, especially by those who did not attend the meeting
  • Expected impact on anti-CD20 mAb usage in their practice was also measured. A 14-22% absolute growth in usage of Gazyva is predicted in the near future, all at the expense of Rituxan usage. No real changes noted in patients not treated with anti-CD20 antibodies or with other anti-CD20 antibodies (not shown). With greater impact seen with non-attendees, this shows the importance of the information itself, compared to the need to be present at the meeting for changing practices.

Use of Maintenance Strategies for Mantle Cell Lymphoma and CLL

Awareness of Abstracts #145, #229 & #230

oncopoll_nhl_maintenance-mcl-cll

General Clinical Importance of Maintenance Strategies for Mantle Cell Lymphoma and CLL

oncopoll_nhl_importance-mcl-cll

Expected Impact on Maintenance Usage in Mantle Cell Lymphoma and CLL

oncopoll_nhl_impact-mcl-cll

Key Conclusions

  • On the same 0 – 5 scale, attendees of the ASH meeting have an average level awareness about these maintenance presentations, while awareness by non-attendees is low
    • No meaningful differences in awareness among these three abstracts
  • Upon providing these abstracts for review, US oncologists recognize the clinical importance of this information and plan on incorporating these maintenance strategies into their clinical practices immediately
    • Meeting attendance does not really impact these findings. In fact, non-attendees may be more likely to use these approaches in their practices

Conclusions: Immediate Impact of 2016 ASH Presentations on Clinical Practice for B-cell Lymphomas

  • All of these studies highlight the importance of the ASH Annual Meeting to the entire hematologic oncology community – awareness of these presentations are high and can occur quite quickly even for those who did not attend the meeting. Alternative methods to disseminate new clinical information are very important to improving clinical practices and patient outcomes
  • The information in these presentations will be integrated into clinical practice in relatively short order, especially since most of these agents are already widely available and in use

For a more detailed analysis report, please click here to download the full report.

Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.

December 07, 2016 - 04:12 pm Posted in ASH Conference Coverage Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) comments0 Comments

By: Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

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Immunotherapies such as checkpoint inhibitors have had a dramatic impact on treatment paradigms for many tumor types over the past few years, and their full potential is far from being realized. Hot on the heels of checkpoint inhibitors are engineered, adoptive T-cell therapies that represent another promising advancement. These “living drugs” certainly have the potential to lead to yet another paradigm shift in anticancer therapies. Chimeric antigen receptor (CAR) technology, one type of adoptive T-cell therapy, took center stage yesterday at the 2016 American Society of Hematology (ASH) annual meeting.

With the CAR T-cell approach, T-cells (typically patient-derived) are transduced with an engineered receptor that typically comprises an extracellular domain that recognizes a specific epitope on cancer cells (typically from a B-cell-derived monoclonal antibody), coupled with the intracellular CD3ζ  domain derived from the T-cell receptor and one or more co-stimulatory signaling domains. Patients receive “preparative chemotherapy” to achieve lymphodepletion and/or myeloablation to minimize regulatory T-cells and myeloid-derived suppressor cells that inhibit immune-mediated attack, and then genetically modified T-cells that attack cancer cells are infused into the patient.

Kite Pharma is developing KTE-C19 (axicabtagene ciloleucel), an investigational therapy where patients’ T-cells are genetically modified to express a chimeric antigen receptor designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. The intracellular portion of the KTE-C19 contains the CD3ζ signaling domain in tandem with the co-stimulatory CD28 signaling domain.

Results of the evaluation of KTE-C19 in patients with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) from the Phase II portion of the ZUMA-1 trial were presented by Dr. Sattva S. Neelapu yesterday in the Late-Breaking Abstract session of the ASH 2016 annual meeting. The ZUMA-1 trial (NCT02348216) is a single-arm, open-label, multicenter, Phase I/II trial designed to evaluate the safety and efficacy of KTE-C19 in refractory aggressive non-Hodgkin’s lymphoma (NHL). Patients with DLBCL, primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) were enrolled in the trial. Safety was the primary endpoint in the Phase I portion of the study, and overall response rate was the primary endpoint of the Phase II portion with secondary endpoints that included duration of response, progression-free survival, and overall survival. Results of the Phase I portion of ZUMA-1 were reported previously1 and demonstrated ongoing complete responses in 43% of treated patients at 12 or more months. The Phase II portion of the study has two cohorts based on tumor type: DLBCL (cohort 1) or PMBCL/TFL (cohort 2). Preliminary results from the first prespecified interim analysis of KTE-C19, which included DLBCL patients (cohort 1), from ZUMA-1 were presented.2

Patients (n=111) were enrolled and leukapheresed to collect T-cells for production of KTE-C19. Patients subsequently received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) x three days. KTE-C19 manufacture was accomplished with an average turnaround time of 17 days, a 99% success rate, and 101 patients each received  a single infusion of KTE-C19 (2 x106 cells/kg).  Patients had a median age of 59 and had received a median of three prior therapies. Of 73 treated DLBCL patients, the best overall response rate (ORR) with a one-month follow-up was 68%, including a complete response (CR) rate of 33%. At a three-month follow-up, the best ORR improved to 76% with a CR rate of 47%, which compares favorably to historical control (p=0.0001), and thus the primary endpoint of the study was achieved. There was a 39% durable CR rate at the three-month assessment. Grade ≥3 adverse events were reported in 93% of DLBCL patients and included cytokine release syndrome in 10 patients (14%) and neurologic events in 18 patients (25%); most of these adverse events were reversible. One KTE-C19-related Grade 5 event was reported in a DLBCL patient.

DLBCL is the most commonly occurring subtype of NHL, with an incidence of 28,449 in 2016 according to Kantar Health’s CancerMPact® Patient Metrics.3 There is a great need for effective treatment options for this patient population as outcomes are quite poor for patients with refractory DLBCL. A recent meta-analysis recently reported an ORR of 26% and median overall survival of 6.6 months based on currently available therapies.4 Efficacy results from the ZUMA-1 study trial far exceed historical controls, like this meta-analysis, and thus ZUMA-1 results generated considerable excitement at ASH 2016. ZUMA-1 is the first multicenter study of anti-CD19 CAR T-cells in refractory, aggressive NHL, and this study demonstrated the successful implementation of management strategies for treatment emergent adverse events associated with this technology. Additional data from ZUMA-1 were presented at ASH 2016 from patients with PMBCL and TFL (cohort 2), and results were equally as encouraging.5

KTE-C19 will likely play an important role in the future treatment of DLBCL and other aggressive NHL subtypes. The U.S. Food and Drug Administration (FDA) awarded KTE-C19 Breakthrough Therapy Designation (BTD) in December 2015. On December 4, 2016, Kite announced that they initiated a rolling submission of a U.S. Biologic License Application (BLA) to the FDA based on the results of ZUMA-1, and completion of the filing is expected by the end of the first quarter of 2017. The BLA is for treatment of relapsed patients with aggressive B-cell NHL who are ineligible for autologous stem cell transplant (ASCT). This submission represents the first BLA filing for a CAR-T therapy. With approval likely, Kite plans to commercially launch KTE-C19 in 2017. Kite also plans a regulatory submission to the European Medicines Agency (EMA) for KTE-C19 in 2017. Earlier this year, the EMA granted Kite access to Priority Medicines (PRIME) regulatory support for axicabtagene ciloleucel for the treatment of refractory DLBCL.

Kite is also sponsoring clinical trials to evaluate KTE-C19 in other B-cell malignancies including indolent NHL, mantle cell lymphoma, acute lymphocytic leukemia, and chronic lymphocytic leukemia. In September 2016, Kite, in collaboration with Roche/Genentech, initiated ZUMA-6, a Phase I/II study designed to evaluate safety and efficacy of KTE-C19 administered in combination with atezolizumab for treatment of patients with refractory DLBCL. The future looks bright for this CAR T-cell product.

References:  

  1. Locke FL, et al. Ongoing complete remissions in phase 1 of ZUMA-1: a phase 1-2 multi-center study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in patients with refractory aggressive B cell non-Hodgkin lymphoma (NHL). Annals Oncol, 27 (suppl. 6):   Abstract 1048O, 2016.
  2. Neelupa SS, et al. KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1. LBA 6, American Society of Hematology annual meeting, 2016.
  3. Kantar Health, CancerMPact® Patient Metrics U.S., accessed December, 2016
  4. Crump M, et al. Outcomes in refractory aggressive diffuse large b-cell lymphoma (DLBCL): Results from the international SCHOLAR-1 study. J Clin Oncol 34, 2016 (suppl; abstr 7516).
  5. Locke FL, et al. A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients With Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL):  Interim Results From ZUMA-1. Abstract 998, American Society of Hematology annual meeting, 2016.

December 05, 2016 - 06:12 pm Posted in ASH Conference Coverage Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) comments0 Comments

By: Len Kusdra, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

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In the management of non-Hodgkin lymphoma (NHL), Rituxan® (MabThera in Europe, rituximab, Genentech/Roche)-based therapy forms the foundation for therapy in all settings. This holds true for most subtypes of NHL, including follicular lymphoma (FL), mantle cell lymphoma (MCL), and diffuse B-cell lymphoma (DLBCL). While Rituxan-based therapy is highly effective and leads to improvement in survival rates, patients are rarely cured, and relapse is common, occurring in about 20-30% of patients.

In addition to this clinical challenge of developing resistance to Rituxan-based regimens, Roche/Genentech also face a commercial challenge as the looming patent expiration for Rituxan approaches and the development of biosimilars threatens to steal Rituxan’s market share. Keeping this in mind, the companies developed an aggressive program with Rituxan’s heir apparent, Gazyva® (Gazyvaro in Europe, obinutuzumab, Roche/Genentech), hoping to maintain their hold in the NHL market. Gazyva is a next-generation CD20 inhibitor designed to be a “biobetter” of Rituxan.

This strategy appeared to have paid off when the Phase III GADOLIN (NCT01059630) trial evaluating Gazyva in combination with Treanda® (bendamustine, Teva/MundiPharma/Symbio) in relapsed patients, presented at the 2015 American Society of Clinical Oncology Conference, showed an improvement in progression-free survival (PFS) when patients were treated with Gazyva plus Treanda followed by Gazyva maintenance.1  Based on these results, Gazyva was subsequently approved in February 2016 for the treatment of FL patients who were refractory to Rituxan-based therapy or had relapsed after Rituxan treatment. The approval propelled Gazyva firmly into the NHL space. (Note that Gazyva is also approved for use in combination with chlorambucil as front-line therapy for chronic lymphocytic leukemia, CLL.) With an approval secured in the relapsed/refractory setting, the question became whether Gazyva would be successful in the front-line setting in patients with FL.

Based on the initial results from the Phase III GALLIUM trial (NCT01332968) presented at the Plenary Session on December 4, 2016, at the American Society of Hematology Conference, the answer appears to be an encouraging “Yes.”2 GALLIUM is an open-label Phase III trial evaluating Gazyva in combination with chemotherapy (CHOP, CVP, or Treanda) followed by Gazyva maintenance versus Rituxan plus chemotherapy followed by Rituxan maintenance. A total of 1,202 patients were randomized to receive Rituxan at 375mg/m2 on day  1 of each cycle or Gazyva at 1000mg on days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (for CHOP and CVP) or six 28-day cycles (for Treanda). Patients who achieved a complete or partial response at the end of induction received 1000mg of Gazyva (for patients in the Gazyva induction arm) or 375mg/m2 of Rituxan (for patients in the Rituxan induction arm) IV every two months for two years or until progressive disease. GALLIUM met its primary endpoint of investigator-assessed PFS. With a median follow-up of 34.5 months, patients in the Gazyva arm had a statistically significant lower risk of progression or death (HR=0.66; 95% CI: 0.51-0.85, p=0.0012). Similarly, PFS as assessed by an independent review committee showed a statistically significant improvement with Gazyva (HR=0.71; 95% CI: 0.54-0.93, p=0.014). While there was a trend toward an overall survival (OS) benefit with the Gazyva arm, showing a 94% three-year OS rate compared with 92% for the Rituxan arm, the data are not mature enough to determine whether this improvement is clinically significant (HR=0.75, 90% CI: 0.49-1.17, p=0.210). The response rates were also similar between the Rituxan and the Gazyva arms (88.5% for Gazyva plus chemotherapy and 86.9% for Rituxan plus chemotherapy).

A post-hoc analysis stratified by combination regimen showed equal survival benefit with Gazyva regardless of the chemotherapy backbone (HR for Gazyva plus Treanda versus Rituxan plus Treanda=0.61; HR for Gazyva plus CHOP versus Rituxan plus CHOP=0.77; HR for Gazyva plus CVP versus Rituxan plus CVP=0.63). Discontinuation rates between both arms were similar (16.3% for Gazyva and 14.2% for Rituxan), as well as rates of Grade ≥ 3 adverse events (74.6% for Gazyva and 67.8% for Rituxan). The most common Grade ≥ 3 adverse events in the Gazyva arm were neutropenia (43.9%), leucopenia (8.6%), febrile neutropenia (6.9%), and thrombocytopenia (6.1%), which were slightly higher than the Rituxan arm. The rates of Grade 5 adverse events were also similar between both arms (4.0% in the Gazyva arm versus 3.4% in the Rituxan arm).

Results from GALLIUM put Gazyva in a favorable position for a line extension in the front-line setting. Roche and Genentech’s design to allow for physician’s choice of chemotherapy may have been out of practical necessity but will ultimately strengthen Gazyva’s utilization. According to physicians surveyed in the United States, CHOP, CVP, and Treanda are the most common partners used in combination with Rituxan, being utilized in over 80% of patients.3 The clinical benefit seen with Gazyva over Rituxan places it in a strong position to absorb a significant market share that Rituxan currently holds not only in the front-line setting but also in the relapsed setting, thus paving the way for a Gazyva-based therapy to replace Rituxan as standard of care in the future. Collectively, these data may thus provide impetus to use Gazyva upfront, with physicians switching the chemotherapy regimen but maintaining Gazyva as backbone following first relapse.

Despite its strong position, Gazyva faces stiff competition. While GALLIUM showed a PFS benefit of Gazyva over Rituxan, the lack of mature OS data may make physicians reluctant to switch to Gazyva, particularly as Rituxan nears the end of its patent lifespan. This may give time to allow entry of potentially lower-cost rituximab biosimilars to corner a share of the market. Indeed, biosimilars of several other branded products have already begun to make entry into the United States with the recent approvals of Zarxio® (filgrastim-sndz, Sandoz), Inflectra® (infliximab-dyyb, Pfizer), Erelzi (enterecept-szzs, Sandoz), and Amjevita (adalimumab-atto, Amgen), and while oncology biosimilars have yet to make landfall in the United States, this may change in the near future as physicians become familiar with these agents.

Highlighting the growing threat that biosimilars pose to branded agents, Sandoz announced earlier this year that the European Medicines Agency accepted a Marketing Authorization Application for a biosimilar to Roche’s Rituxan/MabThera in Europe, signaling the coming battle in the oncology space.4 In addition to biosimilars, Gazyva faces additional threats from novel agents such as Imbruvica (ibrutinib, Abbvie), duvelisib (Infinity), and Revlimid (lenalidomide, Celgene) that are being evaluated in combination with Rituxan in the front-line setting in their respective Phase III trials. Of these agents, the strongest threat to Gazyva appears to be Revlimid, showing a robust response rate when combined with Rituxan (98% ORR) in a Phase II trial of FL patients in the front-line setting.5 If the strong response rate seen in the Phase II trial translates into a survival benefit in the Phase III RELEVANCE (NCT01650701) trial, Revlimid with Rituxan will be in a good position to surpass Gazyva’s current lead in the treatment of FL.

For the time being however, Gazyva represents a leap forward in the treatment of NHL, which is good news indeed for patients.

References: 

  1. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33(suppl; abstr LBA8502).
  2. Marcus RE, Davies AJ, Ando K, et al. Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study. Abstract 6, American Society of Hematology annual meeting, 2016.
  3. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed December, 2016
  4. Sandoz, Press Release May 24, 2016
  5. Fowler NH, Davis RE, Rawal Seema et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 15(12): 1311-8, 2014

This year’s ASH Annual Meeting will be chock-full of interesting, informative, and clinically useful presentations, according to a whirlwind tour of highlights presented at a pre-meeting Webinar by ASH President Charles Abrams, MD, and Stephanie Lee, MD, ASH Secretary.

Starting with the most immediately clinically applicable studies, Dr. Lee singled out two studies of approved agents in narrow disease states: Abstract 182 and 145.

Abstract 182 provides results of the Phase 3 ALCANZA trial comparing brentuximab versus physician’s choice of therapy (methotrexate or bexarotene) in CD30-expressing cutaneous T-cell lymphoma (CTCL), a relatively rare disease. The study included 128 randomized patients followed for 17.5 months. For the primary endpoint, overall response rate (ORR) at 4 months, brentuximab was significantly superior to physician’s choice of therapy: 56% versus 13%, respectively (P<.0001). Median progression-free survival (PFS) was 16.7 months versus 3.5 months, a highly significant difference favoring brentuximab (P<.0001).

“This study showed that brentuximab has a significant advantage over the other two options used to treat CTCL,” Dr. Lee told listeners.

Abstract 145 presents final results of the Phase 3 LyMa trial that compared rituximab maintenance every 2 months for 3 years versus observation in younger patients with mantle cell lymphoma (MCL) in response after undergoing autologous stem cell transplant (ASCT). The study included 240 patients with a median follow-up of 50 months. Four-year event-free survival (EFS) was 78.9% for rituximab maintenance versus 61.4% for observation (P=.0012). Four -year progression-free survival (PFS) and overall survival (OS) were also improved with rituximab maintenance therapy. Four-year PFS was 8.2.% versus 64.6%, respectively (P=.0005), and 4-year OS was 88.7% versus 81.4%, respectively (P=.0413).

“This study provides good evidence that rituximab improves outcomes after ASCT in younger patients with mantle cell lymphoma. Some hematologists are already doing this, and now there is evidence [to support this practice] from a Phase 3 trial,” Dr. Lee noted.

Abstract 6 showed a 34% reduction in risk of progression or death with obinutuzumab versus rituximab as induction and maintenance therapy in about 1200 patients with previously untreated follicular lymphoma with Stage 3 or 4 or bulky Stage 3 disease, according to primary results of the Phase 3 GALLIUM trial.. Patients were randomized 1:1 to obinutuzumab versus rituximab (both anti CD20 agents) at induction. No difference in complete response or partial response was observed after induction therapy. Patients continued on maintenance therapy for 2 years. More Grades 3 and 5 severe adverse events occurred with obinutuzumab.

“These data show that obinutuzumab is more effective in prolonging time to relapse, but the caveat is greater toxicity,” Dr. Lee commented.

CAR-T THERAPY

Dr. Abrams highlighted two studies using genetically engineered chimeric antigen receptor (CAR) T cells. A late-breaker (Abstract LBA 6) showed that Kte-CD19 CAR T cells induced responses in 76% of 101 patients from 22 institutions with refractory diffuse large B-cell lymphoma in the pivotal Phase 2 ZUMA-1 trial. ORR was 76% (47% complete response [CR] rate and 29% partial response rate [PR]). PFS was 56% at 3 months, which Dr. Abrams called “impressive.”

“The T-cells were engineered within 17 days from apheresis, which is a relatively quick turnaround. This treatment is not for the faint of heart, but it does induce complete remissions in some patients. This novel technology can be extended to many centers in the community, even those with no experience using CAR T,” Dr. Abrams noted.

A second study (Abstract 650) found that anti-CD22 CAR T cells had encouraging results in a small study of 9 “tough to treat” patients (children and young adults) with relapsed/refractory acute lymphoblastic leukemia (ALL). All 9 patients had at least 1 prior transplant, and 2 had undergone 2 prior transplants. Patients had chemotherapy and then were given anti-CD22 CAR T. Interim results at 1 month showed that 4 of the 9 patients had CR with no evidence of minimal residual disease.

“This approach with CAR T is a little different, aimed at a different target of T cells with CD 22 expression. This is encouraging, suggesting that the target of CAR T can be expanded. Someday we may be using a panel of targets,” Dr. Abrams commented.

OTHER HEMATOLOGIC MALIGNANCIES

Patients with high-risk chronic lymphocytic leukemia (CLL) were randomized 2:1 to lenalidomide maintenance versus placebo after front-line chemotherapy in the randomized, controlled, German CLLM1 trial (Abstract 229). Interim analysis of the first 89 patients of a planned enrollment of 200 showed such robust results for lenalidomide, that the trial was stopped early. At a median follow-up of 17.7 months, PFS was not yet reached in the lenalidomide-treated group versus 14.6 months for placebo. Patients treated with lenalidomide were 80% more likely to be converted to node-negative disease compared with placebo. No difference in OS was observed between the two groups with short follow-up.

“These interim findings suggest that lenalidomide maintenance is beneficial in high-risk CLL. We need continued follow-up of these patients,” Dr. Lee commented.

Although the investigational drug pacritinib was found effective in myelofibrosis in a Phase 3 trial (Abstract LBA 5), development of the drug was put on hold by the FDA due to potential cardiovascular excess deaths and hemorrhagic events in the PERSIST-1 trial. The Phase 3 PERSIST-2 study evaluated pacritinib versus best available therapy (including the JAK inhibitor ruloxitinib in 44%) in 311 patients with myelofibrosis and platelet counts <100,000 µ/l. Patients were randomized 1:1 to pacritinib versus best available therapy. Pacritinib was superior, with a 35% reduction in spleen volume, and significantly more improvement in time to symptoms at 24 weeks. Although some gastrointestinal and hematologic toxicities were observed with pacritinib, no difference between the two treatment arms was seen in cardiovascular events and bleeding.

PERSIST-2 is the only randomized trial to date in patients with myelofibrosis and thrombocytopenia and prior JAK2 inhibitor exposure. “This study is intriguing. Pacritinib did improve symptoms and spleen volume, but it remains to be seen what the FDA will do,” Dr. Lee said.

Another late-breaking abstract (LBA 1) was based on the randomized, controlled, Phase 3 StaMINA trial, which compared three different approaches to multiple myeloma in transplant-eligible patients using upfront autologous hematologic cell transplant (auto HCT): auto HCT plus RVD (bortezomib, lenalidomide, dexamethasone); tandem auto HCT plus lenalidomide maintenance (TAM); and auto HCT with lenalidomide maintenance (AM). The study enrolled 758 patients. At 38 months, PFS and OS were similar in all three groups. The probability of PFS was 57%, 56%, and 52% for the three approaches, respectively; the probability of OS was 86%, 82%, and 83%, respectively.

This is the largest randomized U.S. transplant trial in myeloma. “Results of StaMINA suggest that the addition of more chemotherapy or more transplant does not improve outcomes. All of these are reasonable approaches,” Dr. Lee noted.

SESSION ON QUALITY

Turning to a different area, Dr. Lee cited a Special Symposium on Quality of Care in the Era of Health Improvement Technology. Three different speakers will tackle the question of whether the new technology is having an impact on patient care.

“I hope this symposium will dig into the current experience for patients and for researchers,” she said.

“There is something for everyone at the upcoming ASH meeting,” she noted.

 

November 21, 2016 - 06:11 pm comments0 Comments

By: Deni Deasy Boekell, Senior Director, Commercial Strategies & Market Access, Kantar Health

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Market forces continue to drive oncology practices to align, invest and adapt to capture patient volume, adjust to decreasing payer reimbursement, optimize revenue, and reduce financial risk.

Affiliation with or even acquisition by an integrated delivery network (IDN) is an attractive option for many practices, offering access to increased patient volume, higher reimbursement through the institution, protection from carrying costs and patient cost-share risk, reduced administrative burden, and inclusion in payment models moving toward integrated patient care.

According to our survey of 150 independent community-based and 80 hospital-owned or -affiliated oncology practices, 35% of independent community oncology practices engaged in some form of business association within the past two years; the majority were affiliations with a hospital/IDN. In addition 22% of oncology practices are considering affiliation with an IDN in the next 24 months.

This means more and more cancer patients are receiving their care through an IDN-affiliated or -owned practice, and those practices are leading investment in capabilities, reimbursement and business models. This shift in oncology care through IDNs is affecting patient treatment in three ways: increasingly centralized management of oncology, focus on cost effectiveness catalyzed by novel reimbursement, and adaptations to increased patient involvement in care planning.

1. IDN centralized management of affiliated oncology practices

Centralized management is being implemented through increasing CPOE/decision support tools to help select drugs, the use of pathways with management controls (e.g., step requirements), and centralized drug acquisition and/or formulary. More than 80% of IDN practice respondents reported being subject to IDN mechanisms that affect prescribing.

IDNs most often use decision support tools, centralized drug formularies and pathways to direct oncologists toward preferred therapies. Pathways are a key mechanism by which IDNs may influence oncologists’ treatment decisions, and IDN oncologists are more likely to be exposed to pathways than are their independent community practice colleagues.

2. Increasing focus on cost effectiveness catalyzed by novel reimbursement

Almost half (46%) of IDN oncologists reported participating in an accountable care organization (ACO) in 2016 (up from 40% in 2015), affecting one-third of their patients on average. ACO-participating IDN practices are more likely to focus on cost-effective treatments, reduction in redundant care, and the quality of life for their ACO patients.

3. Adaptation to increased patient involvement in care planning

While IDN practices most often direct patients with cost concerns to financial support, they do so less frequently than independent community practices. The IDN oncologists are also increasingly looking to less costly drug alternatives in response to affordability issues.

Of note, the 26% response indicating use of less costly drug options in the IDN is up from 13% in 2015.

IDN oncologists are more likely to have end-of-life planning discussions with patients (frequently triggered by changes in patient status) and to have these discussions result in reductions in the use of therapeutic options for most of these patients.

IDNs are structurally different from community practices, and these differences are influencing traditional cancer care delivery and decision making. Given the growing importance of IDNs in oncology care, it’s important to understand how this shift will change cancer care delivery and patient care.

October 25, 2016 - 05:10 pm Posted in Uncategorized comments0 Comments

I have extensive experience in “real world” policy-setting and decision-making and I am puzzled about the motivations regarding the attempt to transfer and recast the failed Quality Adjusted Life Years-based NICE program in the UK to the USA. Among other things, this concern is based upon the findings (Oct. 2014) of the EchOutcome Committee appointed by the European Commission whose chairman concluded that:

“The research provides robust scientific evidence that Quality Adjusted Life Years produce hugely inconsistent, wrong results on which important decisions are being made.”

I add that it has been noted that these wrong NICE-driven decisions have been correlated with decreases in OS across tumor types driving the UK to the “Bottom of the Barrel” in terms of OS across many tumor types compared to other developed Western European countries. Why do we want such a life-threatening process to be transposed to the US by ICER?

Further I note the points (OBR Green on Oct.19) made by 5 eminent Key Opinion Leaders who treat lung cancer every day.

“For us as practicing oncologists and lung cancer researchers, this report has raised serious concerns regarding ICER’s ability to interpret clinical evidence and reach conclusions on drug value that are scientific, comprehensive, and unbiased. ICER appears to represent a perspective that is less oriented toward patient benefit than toward motivations that would limit patient access to new therapeutic options. ICER’s clinic-economic methods include approaches and metrics that, due to their singular focus on population level health, would likely fail patients on an individual clinical needs basis!”

In looking at the roster (Drs. Ettinger, Schwartzberg, Otterson, Jahanzeb, Waterhouse) of experts, I am in full agreement with them. Further, I see many more points that bear extensive examination and discussion. These points include:

  • Across Value Metric Frameworks, including ICER, the failure to use or at least recognize the “Real Price” (e.g., minus 340B and Medicaid discounts) leaves an important piece out of the ICER analysis.
  • Making comparisons and valuations across disparate patient populations (e.g., PD-L1 expression levels) leads to almost absurdly different and misleading comparative values.

Finally, and most importantly, here is a critical lesson that I learned at Aetna making real world decisions daily that directly impacted the lives of 15 million people and that should be duly noted.

“Those who engage in the development of assessments of Evaluation and Valuation must be willing to live with, in an ABSOLUTE manner, (e.g., no appeals, no nothing) the decisions based upon their own assessments realizing that someday such assessments (e.g., ICER) may drive and direct decisions about the treatment of their mother, sister, brother, spouse, children etc.”

by William McGivney, PhD, Managing Principal for McGivney Global Advisors, and former long-time CEO of the NCCN, VP for Clinical and Coverage Policy at Aetna, and Member of the Medicare Coverage Advisory Committee

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