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:
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
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:
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.
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.
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.
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.
Institutional Setting by Attendance of Respondents
Use of anti-CD20 mAbs in the Front Line for Different B-cell Lymphomas
Awareness of Abstracts #6 & #470
General Clinical Importance of Different anti-CD20 mAbs in FL & DLBCL
Expected Impact on anti-CD20 Usage in FL & DLBCL
Use of Maintenance Strategies for Mantle Cell Lymphoma and CLL
Awareness of Abstracts #145, #229 & #230
General Clinical Importance of Maintenance Strategies for Mantle Cell Lymphoma and CLL
Expected Impact on Maintenance Usage in Mantle Cell Lymphoma and CLL
Conclusions: Immediate Impact of 2016 ASH Presentations on Clinical Practice for B-cell Lymphomas
Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.