The OBR Blog

June 24, 2015 - 10:06 am Posted in Featured comments0 Comments

Introduction

In an effort to provide you with timely market feedback from ASCO 2015, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ from the meeting. This first report explored presentations concerning the anti-PD-1 / PD-L1 antibody-based Immune Checkpoint Inhibitors in non-small cell lung cancer (NSCLC).

OncoPoll™ Methodology

  • Primary research phase involved a global survey to verified and validated medical oncologists and multi-disciplinary physicians with an identified clinical interest in lung cancers utilizing targeting parameters within the proprietary MDoutlook® global cancer treater panel
  • Timing: June 2015. Launched 1 week after close of 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., May 29-June 2, 2015
  • Fielding via interactive web-based survey instrument, utilizing proven MDoutlook methodology and proprietary technology
  • Links to discussed abstracts on the ASCO website were provided within the survey
  • Reponses at data collection: 125

Geographic Distribution of Respondents

Attendance at 2014 ASCO Annual Meeting

Key Conclusions

  • Three-fifths of survey respondents attended this year’s ASCO annual meeting
  • Almost all (97%) who attended ASCO went to at least one Lung cancer session
    • 1/3 attended 6 or more sessions on lung cancer


Survey Participants’ NSCLC Cancer Patient Flow:
Average Nearly 20 Cases Each Month

Key Conclusions

  • Survey participants* averaged 57 cases of NSCLC last 3 months
    • Majority of cases involved metastatic disease
  • Non-mutated, Non-squamous NSCLC was the predominate subtype of NSCLC seen

* Survey Participants = Medical Oncologists with an identified clinical interest in NSCLC


Expected Usage of Immune Checkpoint Blockade Antibodies in Non-Mutated NSCLC

Key Conclusions

  • Physicians expect to use immune checkpoint inhibitors in more than half of 2nd line treatment decisions for non-squamous NSCLC. Even higher usage (~2/3) for squamous NSCLC
    • Only 8% of physicians will not use at all in 2nd line for non-squamous NSCLC; only 2% will never use for squamous histology (data not shown)
  • Strong usage of this approach will persist in later lines as well


Expected Usage of Immune Checkpoint Blockade Antibodies in NSCLC with Driver Mutations

Key Conclusions

  • Primary usage of the immune checkpoint inhibitors in NSCLC with driver mutations will be in the 3rd line or later
    • Approximately 1 line later than in NSCLC without the driver mutations
  • Only 5% of physicians will never use this approach with these NSCLC subtypes

Dual Immune Checkpoint Blockade in NSCLC

Key Conclusions

  • Overall calculated average of 6.35
  • More than 1/3 of respondents (38%) rate the clinical impact of these anti-bodies as high / very high


Perceived Value of Immune Checkpoint Blockade Antibodies in NSCLC

Key Conclusions

  • Overall calculated average of 4.74
  • Over ¼ of physicians (27%) perceive the value of these antibodies, at current prices, as being high / very high

Conclusions: Impact of ASCO 2015 on Immune Checkpoint Inhibitors for Lung Cancer

  • The immune checkpoint inhibitors (anti-PD-1/PD-L1) are going to have a very significant impact on the treatment landscape for NSCLC
  • For cases of NSCLC without driver mutations, treatment with these antibodies is expected to become the primary 2nd line treatment option
    • Nearly 2/3 of squamous NSCLC patients will receive an anti-PD-1/PD-L1 antibodies in the 2nd line
    • About half of non-squamous NSCLC will receive this therapeutic approach in the 2nd line
    • Usage declines in later lines but still remains at respectable levels (20-30% of patients)
  • For cases of NSCLC with driver mutations (ALK+ or mutated EGFR), usage of the anti-PD-1/PD-L1 antibodies will still occur, albeit in 1 later line of therapy (primarily starting in 3rd line)
  • Combining the anti-PD-1/PD-L1 antibodies with the anti-CTLA-4 antibody ipilimumab is seen as a promising approach that will further impact treatment paradigms in the future
  • At today’s prices, physicians see good value in using the anti-PD-1/PD-L1 antibodies for NSCLC
    • 27% of respondents rate their value in NSCLC as high or very high
    • 38% of respondents rate their clinical impact in NSCLC as high or very high

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

Submitted by Robert Stephan, Sr. Director Medical Services and Strategy, and Jan Heybroek, President MDoutlook.

June 02, 2015 - 03:06 pm Posted in ASCO Conference Coverage comments0 Comments

By Mara Jeffress, Ph.D., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

The number of agents available to treat relapsed/refractory myeloma has expanded rapidly over the past three years, with the launch of next-generation proteasome inhibitor Kyprolis® (carfilzomib, Onyx /Amgen, accelerated FDA approval July 2012) and the next-generation immunomodulator Pomalyst® (pomalidomide, Celgene, FDA approved February 2013) as monotherapies, and the HDAC inhibitor Farydak® (panobinostat, Novartis, accelerated FDA approval February 2015) for use in combination with bortezomib + dexamethasone (VelDex). These three agents add to the long-established standards of care, Velcade® (bortezomib, Millennium/Takeda) and Revlimid® (lenalidomide, Celgene), which are used in both newly diagnosed and relapsed/refractory patients. Pivotal data for Kyprolis and two new agents ― elotuzumab (AbbVie/Bristol-Myers Squibb) and daratumumab (Genmab/Janssen) ― were presented on Tuesday at the Myeloma Oral Session of the American Society of Clinical Oncology (ASCO) annual meeting.

Based on the results of a large Phase II program, Kyprolis was granted FDA accelerated approval as a monotherapy for myeloma patients who have received prior therapy with an immunomodulatory agent and proteasome inhibitor. It is now the most commonly used third-line agent, used in one-third of patients.1 As a second-generation proteasome inhibitor, the ability of Kyprolis to gain use in earlier lines of therapy will hinge on demonstrating benefit in comparison with the entrenched first-generation proteasome inhibitor, Velcade. The Phase III ENDEAVOR trial compared Kyprolis (at a dose of 56 mg/m2, twice the currently approved monotherapy dose of 27 mg/m2) plus dexamethasone (KypDex) versus VelDex in 929 patients who have received one to three prior lines of therapy (50% were second-line, 33% were third-line and 17% were fourth-line). Progression-free survival (PFS) was significantly improved, with the KypDex arm doubling PFS at the median compared to VelDex (median PFS 18.7 versus 9.4 months, HR=0.53, p< 0.0001).2 Overall survival (OS) data were immature; however, a slight trend to benefit was suggested in the data presented (HR=0.79, p=0.66). Overall response rates (ORR) also favored Kyprolis: 77% versus 63% (p< 0.0001); 54% versus 29% had a very good partial response or better, and 13% versus 6% of patients had a complete response. Responses were robust even in patients treated with prior Velcade. Treatment discontinuation (14.0% vs. 15.7%) and on study death (3.9% vs. 3.4%) due to an adverse event (AE) occurred at similar frequencies in each arm. Grade 3/4 hypertension (8.9% vs. 2.6%), dyspnea (5.6% vs. 2.2%), cardiac failure (4.8% vs. 1.8%) and acute renal failure (4.1% vs. 2.6%) were all increased in the KypDex arm. Considering the fact that patients in this trial were receiving double the approved monotherapy dose, the AEs perhaps aren’t unexpected, although they are still concerning when considering the use of this regimen in the general population of myeloma patients outside of a highly selected clinical trial. These increased toxicities were balanced by a significant decrease in Grade 2 or higher peripheral neuropathy (6.3% vs. 32.0%, p< .0001), which is all the more encouraging considering that the majority (79%) of patients in the control arm received subcutaneous (SC) Velcade, which has lower rates of neuropathy compared to the intravenous (IV) formulation.

The near doubling of PFS over VelDex will establish KypDex as a new standard of care, especially if OS data is positive. The positive results from ENDEAVOR should only serve to strengthen Kyprolis’ share in third-line and help it gain share in second-line, where VelDex is currently utilized in one-third of patients.1 The positive results of ENDEAVOR come just six months after another positive Phase III trial for Kyprolis – the ASPIRE trial, which showed that patients receiving Kyprolis combined with lenalidomide + dexamethasone (RevDex) had a median PFS of 26.3 months compared to a median PFS of 17.6 months for patients treated with RevDex alone (HR=0.69; p=0.0001).3 Together, these two trials raise questions about where Kyprolis will fit in the treatment paradigm – as a doublet or a triplet, and in which line of therapy?

While Kyprolis, at least in ENDEAVOR, is challenging Velcade head-to-head, elotuzumab is choosing to combine with one of the current standard-of-care treatment regimens, RevDex. Elotuzumab is an anti-SLAMF7 monoclonal antibody that has FDA Breakthrough Therapy Designation for relapsed/refractory multiple myeloma and is being studied in two Phase III trials, both in combination with RevDex, in the front-line and relapsed/refractory settings. In the relapsed setting, the results of the ELOQUENT-2 trial compared elotuzumab in combination with RevDex versus RevDex alone in 646 patients who had received a median of two prior therapies, including Velcade (70%), thalidomide (48%) and Revlimid (6%). Revlimid-refractory patients were excluded from enrollment. Elotuzumab given with RevDex extended PFS by a median of 4.5 months compared with RevDex alone (median PFS 19.4 vs. 14.9 months, HR = 0.70, p = 0.0004). In addition, one-year PFS was 68% versus 57% and two-year PFS was 41% versus 27%. ORR also favored the addition of elotuzumab (79% vs. 66%, p = 0.0002).4 OS is still immature and was not reported, but the presenter, Dr. Lonial, suggested the results, which will be available in the fourth quarter of 2015, were trending toward the positive. There were no significant increases in toxicity except for Grade 3/4 lymphopenia (77% vs. 49%) and increased incidence of Grade 1-3 infusion reactions (10% vs. 0%); Grade 3/4 neutropenia was lower in the elotuzumab arm (34% vs. 44%). A large number of high-risk patients were enrolled in the trial (32% del17p and 10% t(4;14)), and subgroup analysis showed that PFS was robust even in these subgroups (HR=0.65 for del17p and HR=0.53 for t(4;14)). While important to understand that the regimen provides benefit in these subsets, it does create difficulties for cross-trial comparisons.

Acknowledging the trial demographic differences, a comparison of ELOQUENT-2 with outcomes for KypDex and Kyprolis + RevDex suggests that elotuzumab + RevDex might provide a comparable median PFS and ORR as is achieved with KypDex (although the Hazard Ratio was better for KypDex), and inferior median PFS and ORR compared to KypRevDex (comparison is difficult here as fewer patients (12.6%) in ASPIRE were high-risk, which may have boosted the mPFS); however, the AE profile appears most benign for elotuzumab in combination with RevDex. A key advantage of elotuzumab is its novel mechanism of action and its combinability with other agents due to its relative mild toxicity profile. While these advantages may give elotuzumab a strong positioning stance in newly diagnosed patients, competitive pressures are stronger in relapsed myeloma. Most significant may be the changing backbone of care across the lines of therapy (choice of immunomodulator or proteasome inhibitor or both), which may leave fewer opportunities for use of elotuzumab if its approval in the relapsed/refractory setting is tied to the RevDex combination.

Elotuzumab is aiming to be the first monoclonal antibody used to treat multiple myeloma. Competition will come quickly from another antibody known as daratumumab. Daratumumab is a human monoclonal antibody directed against CD38, which is highly expressed on the surface of multiple myeloma cells. Daratumumab has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis. Based on promising early data, the FDA granted Breakthrough Therapy Status to daratumumab for treatment of double-refractory multiple myeloma.

Daratumumab, at least initially, is taking a slightly different development tactic than either Kyprolis or elotuzumab and is hoping to enter the myeloma market initially by targeting fourth-line or later patients.5 An open-label, two-part Phase II study (Sirius, MMY2002, NCT01985126) evaluated daratumumab monotherapy in its FDA breakthrough therapy designation population: double-refractory myeloma patients with at least three prior lines of therapy. In part 1, 34 patients were randomized to daratumumab 8 mg/kg (n = 18) or 16 mg/kg (n = 16) to determine the most effective dose. In part 2, 90 additional patients were given the 16 mg/kg dose. Data for 106 heavily pretreated (median five prior lines, including 95% double refractory and 66% refractory to three of four approved agents (Revlimid, Velcade, Pomalyst and/or Kyprolis)) patients were reported. After a median follow-up of 9.3 months, 29% of patients responded to daratumumab, including three complete responses, 10 very good partial responses, and 18 partial responses. Responses to daratumumab were rapid and durable, lasting on average 7.4 months. Response was consistent across all subgroups including the most refractory patients. Median PFS was 3.7 months. Median OS has not been reached, and the estimated one-year OS rate is 65%, which is remarkable in such a refractory population. Common all-grade AE (≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%) and cough (20.8%). Infusion-related reactions were common (43%) but mainly Grade 1/2 (5% Grade 3; 0% Grade 4). J&J intends to seek accelerated approval for daratumumab later this year6 and already has plans to enter the ranks of emerging triplet therapies in myeloma, by initiating two Phase III trials in relapsed/refractory patients combining daratumumab with VelDex (NCT02136134) or with RevDex (NCT02076009). The discussant, Dr. Lentzsch, enthusiastically reviewed the Phase I/II data showing that daratumumab plus RevDex had an impressive 87% ORR with responses that deepened over time.

Given the increasingly crowded relapsed/refractory setting, companies that plan to bring more agents to multiple myeloma will need to go head-to-head against or combine with RevDex, VelDex, KypDex or the various established and emerging triplet regimens. As we have seen in other crowded markets such as renal cell carcinoma, even existing approved agents may be forced into head-to-head trials to establish dominance and win a significant portion of the market. As of now, there is no clear winner, and the influx of new agents will only confuse matters more with the lack of understanding of whether triplets are better than doublets, if quadruplets are better than triplets (this is sure to be explored in the near future), which regimen is superior and how to sequence the drugs. Furthermore, across all scenarios also exists the question of cost of care. Can the market (and patients) afford combination therapies that continue to push the boundaries of affordability? The price may be justified if the new combination therapies can provide a long-term survival benefit, but for now the regimens reported here have only firmly established a PFS benefit.

References:

1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 1, 2015.

2. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR. J Clin Oncol. 2015;33(suppl; abstr 8509)

3. Stuart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. NEJM, 372(2): 142-52, 2015.

4. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33(suppl; abstr 8508)

5. Lonial S, Weiss BM, Usmani SZ et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33(suppl; abstr LBA8512)

6. Johnson & Johnson press release, May 20, 2015.

June 02, 2015 - 02:06 pm Posted in ASCO Conference Coverage comments0 Comments

By Arnold DuBell, Ph.D., M.B.A., Consultant; Elizabeth Clarke, Ph.D., M.P.H., Analyst; Stephanie Hawthorne, Ph.D., Senior Director; Len Kusdra, Ph.D., Analyst; and Gregory Wolfe, Ph.D., Senior Consultant – Clinical & Scientific Assessment, Kantar Health

Immunotherapy has dominated the conversation in oncology for the past several years, and the excitement still hasn’t waned at all — in fact, it continues to grow. New drugs have entered development in this space, new mechanisms of action have emerged, and new tumor types have become the focus of our attention. We have previously seen various levels of evidence to support the activity of checkpoint inhibitors in melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, breast cancer, gastric cancer, head and neck cancer and Hodgkin’s lymphoma. At this year’s annual meeting of the American Society of Clinical Oncology (ASCO), we observed first reports of the activity of several PD-1 and PD-L1 inhibitors in multiple new tumor indications, adding to the growing body of evidence that suggests immunotherapy is closely approaching panacea status.

Hepatocellular carcinoma

Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) was studied in a global Phase I/II trial in patients with advanced hepatocellular carcinoma (HCC).1 This was a dose-escalation study, and it also stratified patients according to their hepatitis B/C viral (HBV, HCV) infection status (uninfected vs. HCV-infected vs. HBV-infected). The majority of patients (75%) had received prior systemic therapy for their disease, with most (68%) having received prior Nexavar® (sorafenib, Onyx/ Amgen/Bayer). At this interim analysis of 42 evaluable patients, single-agent Opdivo produced a 19% objective response rate (ORR; which was measured across all dose cohorts), including two patients (5%) with a complete response; an additional 48% of patients had stable disease. Responses were seen in all patient cohorts, but the response rate was higher in those with HCV infections (36%). It was postulated that perhaps patients with higher viral load/disease burden are more sensitive to PD-1 inhibition and speculated that HCV T-cells may naturally express higher levels of PD-L1, making them more sensitive to PD-1 inhibition; both of these observations are very preliminary in nature, however, and need more data to fully understand whether there is a correlation with activity and, if so, why. The duration of responses were very encouraging (out to one year in some patients) and the one-year overall survival (OS) rate was 62% — unheard of in metastatic, relapsed HCC! These are exciting data in a tumor of very high unmet need, and we’re looking forward to following this trial for the final results and monitor for future clinical development in this indication.

Esophageal

There has been little development of targeted therapies for esophageal cancer, making it a tumor of small incidence but large unmet need. Immunotherapy agents have already shown promise in gastric and gastroesophageal junction adenocarcinoma, so it was nice to see a presentation describing the first data for this class in patients with metastatic esophageal cancer. An expansion cohort of the Phase Ib KEYNOTE-028 trial enrolled 23 patients with primarily PD-L1-positive, heavily pretreated esophageal cancer (a few patients had gastroesophageal carcinoma).1 Treatment with single-agent Keytruda® (pembrolizumab, Merck & Co.) was associated with a 30.4% partial response rate (29.4% in the 17 patients with squamous cell carcinoma and 40.0% for the five patients with adenocarcinoma). Responses are very durable, with an average duration of response of 40 weeks. More than half of patients showed some degree of tumor shrinkage. These are excellent outcomes, especially considering that a 30% response rate isn’t much different than that usually seen in the first-line setting for gastroesophageal cancer. However, the discussant, Dr. Fuchs, emphasized slight caution due to the lack of central review in this trial. Similar to other trials for Keytruda, adverse events (AEs) were very limited, with only four patients (17.4%) experiencing Grade 3 toxicities. During the discussion, Dr. Fuchs hypothesized on why these patients seemed to respond so well to Keytruda. Although the patients with the Epstein-Barr virus (EBV)-positive and microsatellite instability (MSI)-positive2 adenocarcinoma subtypes might be responding to increased immune activity due to association of these subtypes with increased PD-L1 expression, the responses in patients with squamous cell carcinoma may be associated with the high degree of DNA focal copy number alterations. Further research is warranted to evaluate these hypotheses as well as confirm the encouraging activity of Keytruda in these patients.

Ovarian Cancer

Today results were presented from two separate Phase Ib studies that are evaluating safety and efficacy of PD-1 checkpoint inhibitors in patients with relapsed/refractory ovarian cancer. In the first of the two trials,3 75 heavily pretreated ovarian cancer patients enrolled in an expansion cohort were treated with the PD-L1 inhibitor avelumab (Merck KGaA/Pfizer). Patients were not selected based on PD-L1 status. There were no complete responses, and eight patients achieved partial responses for an ORR of 10.7%. Stable disease was the best response in 33 patients, for a clinical benefit rate of 54.7%. Responses were ongoing in five of eight patients, and the median duration of response was nine weeks. Grade 3/4 adverse events were reported in six patients (8%), and the most common treatment-related AEs of any grade included fatigue (16.0%), chills (12.0%), nausea (10.7%) and diarrhea (10.7%). The author noted that a Phase III trial of avelumab is currently being planned. The second presentation reported results from the ovarian cancer cohort (n=26) of the Phase 1b KEYNOTE-028 trial.4 Heavily pretreated, PD-L1-positive patients were enrolled in KEYNOTE-028 and received the anti-PD-1 antibody Keytruda, and they were treated for 24 months or until disease progression. The ORR was 11.5% and included one complete response and two partial responses. Another six patients achieved stable disease for a disease-control rate of 34.6%. Median duration of response was not reached. Grade 3/4 AEs were reported in 3.8% of the patients, and the most common treatment-related AEs included arthralgia (23.1%), diarrhea (11.5%) and nausea (11.5%). The authors are further analyzing their data to discern whether there is a relationship between PD-L1 expression and activity. These two studies demonstrate that both anti-PD-1 and anti-PD-L1 antibodies are well-tolerated and active in heavily pretreated ovarian cancer patients. Interestingly, the ORR was similar between the two trials; therefore, as with other indications, physicians may need to wait for follow-up data to determine the ultimate choice of immunotherapy option.

Glioblastoma

Another example where immunotherapies may make an impact is in recurrent glioblastoma multiforme (GBM), which has a poor prognosis when treated with current therapies and thus represents a considerable unmet need. PD-L1 expression has been associated with high-grade but not low-grade gliomas.5 Also, antitumor activity using a non-commercial anti-PD-1 monoclonal antibody was observed in mouse glioma models.6 Given this preliminary data, Bristol-Myers Squibb (BMS) initiated the Phase III CheckMate-143 trial, which will randomize patients to Opdivo or Avastin® (bevacizumab, Genentech/Roche/Chugai) after progression following surgical resection, radiation and temozolomide. The design of CheckMate-143 included a safety run-in phase evaluating Opdivo with or without Yervoy® (ipilimumab, BMS), which reportedly helped influence the Phase III trial design; some of this data from 20 patients were presented in a poster session at ASCO 2015.7 Note that the arms containing Yervoy were included based on activity observed for Yervoy in patients with melanoma and brain metastases.8 In the data just presented, treatment-related serious AEs occurred in two patients in the monotherapy arm and seven patients treated with the combination. Moreover, as might be expected, the combination regimen had more treatment-related discontinuations (40% vs. 0%). With this said, Opdivo monotherapy was very well tolerated. Opdivo monotherapy was associated with a 10% partial response (PR) rate and a 50% clinical benefit rate; six- and nine-month OS rates were 70% and 60%, respectively. In contrast, Opdivo plus Yervoy was associated with no PRs and a 40% stable disease rate; six- and nine-month OS rates were 80% and 60%, respectively. Given this data, Opdivo monotherapy was chosen to be evaluated in the Phase III trial initiated last year. With the limited options currently available for GBM patients, there should be a high level of enthusiasm to quickly see the outcome from this trial.

Small Cell Lung Cancer

Checkpoint inhibitors are active in other thoracic tumors. Opdivo is already approved for use in non-small cell lung cancer (NSCLC) patients with squamous histology and recently excited ASCO attendees with the CheckMate-057 data in patients with non-squamous histology. Keytruda also showed strong promise in both NSCLC in the KEYNOTE-001 trial and malignant pleural mesothelioma in an expansion cohort of the Phase Ib KEYNOTE-028 trial. Given the level of competition between the two molecules in these other thoracic tumors, it is not surprising to see data for both agents in small cell lung cancer (SCLC). A different cohort from Keynote-028 examined the safety and preliminary efficacy of Keytruda in 20 patients with PD-L1-positive relapsed SCLC.9 The toxicity profile was mild, with 10% of patients having Grade 3 or greater AEs; one fatality occurred due to Grade 5 colitis. There was promising evidence of efficacy, with seven (35%) evaluable patients achieving a partial response. Median time to response was 8.6 weeks, with six of seven responses ongoing at the time of data cutoff; one patient has exhibited a response of at least 32 weeks. Opdivo was evaluated in the CheckMate-032 trial, a Phase I/II trial randomizing 90 heavily pretreated SCLC patients to Opdivo with or without Yervoy.10 The combination was evaluated at two dose levels: Yervoy dosed at 1 mg/kg or 3 mg/kg. The most common Grade 3/4 side effects in patients receiving Opdivo plus Yervoy included diarrhea (8.5%), increase in lipase (6.4%), rash (4.3%) and vomiting (4.3%); the total incidence of Grade 3/4 toxicities was 15% for the monotherapy and 34% for the combinations. The initial ORR for Opdivo monotherapy was 18% (CR 0%) and for both combinations was 17% (CR 2%). The ORR for the combination increased with continued treatment, as seven patients with initial stable disease were upgraded to confirmed partial responses, resulting in an ORR of 32.6%. Subgroup analysis showed that this level of response was found in both platinum-sensitive and platinum-resistant patients. Median duration of response was 6.9 months for the combination and was not reported for the monotherapy. Median OS was 4.4 months for Opdivo monotherapy and 8.2 months for the combination. Neither trial showed evidence of a linkage between increased PD-L1 expression and activity. Although Keytruda showed a higher level of activity than Opdivo monotherapy (35% versus 18%), the numbers of patients and the inability at this stage to assess how similar the patient populations are will force physicians to wait for further data in this indication to help them make choices as to which immunotherapy to offer their SCLC patients.

Colorectal

In the original Phase I trial for Opdivo presented at ASCO 2012,11 no responses were observed among 19 patients with colorectal cancer (CRC). At ASCO 2015, however, data presented from a new Phase I trial suggests a subset of these patients may actually benefit from PD-1 inhibition. In a multicohort Phase II trial, patients with pretreated CRC were enrolled into two cohorts – those with tumors proficient for mismatch repair (MMR; n=25, n=25 evaluable) and those with MMR-deficient tumors (n=25; n=13 evaluable); a third cohort enrolled patients with MMR-deficient non-colorectal pretreated solid tumors (n=21; n=10 evaluable). Activity was strikingly different among these cohorts of patients following treatment with Keytruda. The ORR was 62% in MMR-deficient CRC patients and 60% ORR in MMR-deficient non-colorectal cancers, but the ORR was 0% in patients with MMR-proficient CRC. The difference can’t be blamed on the depth of response, because disease control including stable disease was equally different: 92% in MMR-deficient CRC, 70% in MMR-deficient non-colorectal cancers, and only 16% in MMR-proficient CRC. Progression-free survival and OS were also longer in patients with MMR-deficient CRC or other cancer compared to patients with CRC-proficient tumors. Although the sample sizes of MMR-deficient CRC and MMR-deficient non-CRC cohorts were small, and there was a slight imbalance in patient demographics between the cohorts (MMR-proficient CRC patients were older and slightly more pretreated), the degree of differential efficacy seems large enough to suggest the correlations may be real. Additional analysis shows that MMR-deficient tumors have greater density of invasive CD8+ T-cells, greater density of PD-L1-positive invasive CD8+ T-cells, and more somatic mutations per tumor than MMR-proficient tumors. Together, these data point to a possible mechanistic explanation for the differential activity of Keytruda, wherein higher tumor mutational burden leads to greater immune system recognition and tumor infiltration, leading to improved activity of PD-1 inhibitors.

This theory explains the exquisite activity of checkpoint inhibitors that has been observed in melanoma, NSCLC, bladder cancer, SCLC, gastric cancer, esophageal cancer and head and neck cancer: These tumors have the highest somatic mutational burden according to data from the Cancer Genome Project.12 Although mutational load is unlikely to be the only factor that influences likelihood of response to checkpoint blockade, new data from ASCO 2015 suggest it certainly plays a role and may need to be considered for future development plans and eventually patient selection across a number of solid tumor types.

References:

1. El-Khouery AB, Melero I, Crocenzi TS, et al.; “Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040;” J Clin Oncol 33, 2015 (suppl; abstr LBA101).

2. MSI: microsatellite instability; EBV: Epstein-Barr Virus

3. Disis ML, Patel MR, Pant S, et al.; “Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory: a phase Ib open label expansion trial;” J Clin Oncol, 33 (suppl., abstr 5509), 2015.

4. Varga A, Piha-Paul SA, Ott PA, et al.; “Antitumor activity and safety of pembrolizumab in patients with PD-L1 positive ovarian cancer: interim results for a phase 1b study;” J Clin Oncol, 33 (suppl., abstr 5510), 2015

5. Yao Y, Tao R, Wang X, et al.; “B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells;” Neuro Oncol, 11:757–766, 2009.

6. Zeng J, See AP, Phallen J, et al.; Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas;” Int J Radiat Oncol Biol Phys, 86: 343-349, 2013.

7. Sampson JH, Vlahovic G, Sahebjam S, et al.; “Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CheckMate-143; J Clin Oncol, 33 (15_supp), Abst 3010, 2015.

8. Margolin K, Ernstoff MS, Hamid O, et al.; “Ipilimumab in patients with melanoma and brain metastases: an open-label phase 2 trial;” Lancet Oncol, 13:459-465.

9. Ott PA, Fernandez MEE, Hiret S, et al.; “Pembrolizumab in patients with extensive-stage small cell lung cancer: Preliminary safety and efficacy results from KEYNOTE-028;” J Clin Oncol. 33 (suppl. Abstr 7502), 2015.

10. Antonio SJ, Bendell JC, Taylor MH, et al.; “Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer: CA209-032;” J Clin Oncol. 33 (suppl. Abstr 7503), 2015.

11. Le D, Uram J, Wang H, et al.; “PD-1 blockade in tumors with mismatch repair deficiency;” J Clin Oncol 33, 2015 (suppl; abstr LBA100).

12. Alexandrov LB, Nik-Zainal S, Wedge DC, et al.; “Signatures of mutational processes in human cancer;” Nature 2013, 500: 415-421.

June 02, 2015 - 12:06 pm Posted in ASCO Conference Coverage comments0 Comments

By Arnold DuBell, Ph.D., M.B.A., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

In several B-cell malignancies, physicians have a number of new options for their patients, allowing these patients the promise of being treated for several lines of therapy. For chronic lymphocytic leukemia (CLL) and indolent lymphoma patients, physicians now have the option to use kinase inhibitors such as Imbruvica® (ibrutinib, Pharmacyclics/Janssen) or Zydelig® (idelalisib, Gilead). For multiple myeloma patients, physicians now have the option to utilize Kyprolis® (carfilzomib, Amgen/Onyx) or Pomalyst® (pomalidomide, Celgene). However, patients do ultimately progress even after being treated with these new agents. A Clinical Science Symposium held during the annual meeting of the American Society of Clinical Oncology (ASCO) presented early-stage data for a set of agents that give hope that this gap might be filled: chimeric antigen receptor (CAR) T-cell therapies. The fact that three abstracts on early-phase data were reviewed in a symposium dedicated to this novel mechanistic class of therapies speaks to the level of excitement this mechanism of action (MOA) is eliciting from the oncology and hematology communities.

CARs are synthetic, engineered receptors that can target cell surface antigens expressed by tumor cells. For many B-cell malignancies, a target has been most studied with this class of agents is CD19. These engineered receptors can be stably expressed on primary T-cells, allowing the engineered T-cell to dock with and kill tumor cells containing the antigen target of interest. Moreover, second and third generations of CAR-T therapies are being developed, including CD3ζ (to improve cytotoxicity), CD28 (to improve proliferation and cytokine production) and motifs such as 4-1BB or OX40 (for co-stimulatory functionality). As Dr. Ansell suggested as part of his “CAR-T 101” presentation, these “super T-cells” (not his words) will hopefully provide better responses than normal T-cells through enhanced tumor cell recognition, forced T-cell activation and increased T-cell persistence.

There were three clinical presentations during this session: two evaluating CAR-T therapies in patients with B-cell lymphomas and one evaluating a CAR-T therapy in patients with multiple myeloma. In the first presentation,1 a CAR-T therapy with only CD-28 and CD3ζ motifs (19-28z, Memorial Sloan Kettering/Juno Therapeutics) was used to treat 11 patients with relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma (NHL) after high-dose therapy and autologous stem cell transplantation (ASCT). This study was primarily designed to determine a safe dose to use for Phase II trials. The primary toxicity for this therapy was cytokine release syndrome (CRS), reported in seven patients, and this toxicity was dose-limiting in one patient. Although the post-ASCT design of this trial makes it difficult to firmly evaluate the efficacy contribution of 19-28z CAR-T, it is quite encouraging to note that four of 10 evaluable patients remain in complete remission (40%) for durations of at least 13 to 21 months.

The second presentation evaluated a different CAR-T construct in 22 heavily pretreated CD19+ lymphoma patients (13 DLBCL, 7 FL, 2 MCL).2 The construct used to generate the CAR-T therapy (CTL019; Novartis/University of Pennsylvania) contained CD-28, CD3ζ and 4-1BB motifs. The activity of the therapy was very promising in diffuse large B-cell lymphoma (DLBCL) patients: the best response rate (at three months) was 50%, with five out of six patients remaining in CR for at least six months and two responses lasting longer than a year. Of the seven evaluable follicular lymphoma patients treated with CTL019, the response rate was 100%, includingsix patients in CR at six months. To date, only two mantle cell lymphoma (MCL) patients have been enrolled, so efficacy data is very immature. Among all patients, the primary Grade 3 or higher toxicities were lymphopenia (18 patients), neutropenia (nine patients) and leucopenia (five patients). Two patients had Grade 3 or higher cytokine release syndrome (CRS), while delirium and encephalopathy occurred in one patient each.

The final abstract evaluated CTL019 in 10 patients with advanced multiple myeloma.3 This tumor type is an interesting choice for a CD19-derived CAR-T, as the majority of myeloma cells are CD19-negative. The presenter (Dr. Garfall) speculated on several rationales for this Phase I pilot study: the presence of clonotypic CD19+ B-cells or a subset of drug-resistant CD19+ cells, as well as a few cells in the dominant CD19 population with diminished copy number of cell-surface CD19 (CD19-dim). The 10 patients were already treated with ASCT and multiple lines of chemotherapy, and then treated with ASCT again along with administration of CTL019. With more than 100 days of follow-up, evidence of clinical benefit was observed in three of four evaluable patients. Moreover, two of these patients had longer and deeper responses than what they had experienced with their prior ASCT, suggesting efficacy contribution attributable to CTL019.

Although this technology is very promising, several technical hurdles remain to be solved. The two hurdles noted most often by the speakers were the persistence of the engineered T-cells and reducing the CRS and central nervous system toxicities. The last speaker (Dr. Avigen) provided current pre-clinical research – for example, addition of suicide genes within the CAR cassette to abrogate CAR-mediated toxicity, or the co-administration of select interleukins to increase persistence – that may solve some of these issues. However, the real question is whether CAR-T therapies are ready to make an impact within the next few years. In certain cases the answer appears to be a resounding “yes,” as there have been other promising data in other disease types, most notably acute lymphoblastic leukemia as well as the promising data presented at ASCO 2015 in B-cell lymphomas. However, the data presented at the ASCO Clinical Science Symposium also suggest that for other tumors types, such as multiple myeloma, the technology is not ready to let oncologists “drive your CAR-T therapy.”

References:

1. Sauter, Abstract 8515, ASCO 2015

2. Schuster, Abstract 8516, ASCO 2015

3. Garfall, Abstract 8517, ASCO 2015

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