In an effort to provide you with timely market feedback from the 2016 ASCO Annual Meeting, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report explores presentations concerning the sidedness of the primary tumor in metastatic colorectal cancer(mCRC) and the potential use of gemcitabine + capecitabine (GEMCAP) as adjuvant therapy in resected pancreatic cancer patients.
For a more detailed analysis report, please click here to download the full report.
Submitted by Robert Stephan, VP, Research and Physician Society, and Jan Heybroek, President MDoutlook
By: Tari Awipi, Ph.D. Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Arnold DuBell, Ph.D., M.B.A., Senior Consultant, Clinical & Scientific Assessment, Kantar Health
The CDK 4/6 inhibitor Ibrance® (palbociclib, Pfizer) burst onto the scene in February 2015 with its original approval from the U.S. Food and Drug Administration (FDA) for treatment of newly diagnosed HR+/HER2- breast cancer. This accelerated approval, based on the Phase II PALOMA-1 trial, was contingent on a post-marketing Phase III trial, PALOMA-2. Yesterday the positive results of PALOMA-2 were presented at the American Society for Clinical Oncology (ASCO) annual meeting and confirmed the 10-month improvement in progression-free survival (PFS) (10.2 months versus 20.2 months, HR 0.49, p=0.0004) in patients with HR+/HER2- advanced breast cancer reported in PALOMA-1.1,2
As it was partly confirmatory, PALOMA-2 had a similar design. In PALOMA-2, 666 previously untreated HR+/HER2- breast cancer patients were randomized to Ibrance or Ibrance plus letrozole or placebo plus letrozole. Similar to PALOMA-1, the addition of Ibrance was associated with a 10.3-month improvement in PFS (investigator-assessed medians: 24.8 months versus 14.5 months; HR 0.58, p=0.0004). Independent central review suggested a similar benefit (30.5 months versus 19.3 months, HR 0.65, p=0.0005). In the intent-to-treat population, Ibrance improved the objective response (42% versus 35%, OR 1.40, p=0.031) and the clinical benefit rate (85% versus 70%, OR 2.39, p<0.0001). Overall survival data were not presented. Ibrance primarily increased the incidence of Grade 3-4 neutropenia (66% versus 1%) and leucopenia (25% versus 0%). This is represented in the minor increase in the adverse event-associated treatment discontinuation rate (9.7% versus 5.9%). One factor that was highlighted in both the presentation and the discussion was that the data from the Phase III PALOMA-2 trial were strongly consistent with the data from the Phase II PALOMA-1 trial (see table below). This consistency confirms not only the statistically significant efficacy benefit for Ibrance but also the strong clinical relevance of this efficacy benefit.
|Trial Design||Phase II, open-label||Phase III, placebo control|
|Patients on Study||165||666|
|Median PFS (months)||20.2 versus 10.2 months
(10 month improvement)
|24.8 versus 14.5 months
(10.3 month improvement)
|ORR (ITT)||43% versus33%||42% versus 35%|
|CBR (ITT)||81% versus 58%||85% versus 70%|
|Source: (1) Finn, Lancet Oncol, 2015; (2) Finn, Abstract 507, ASCO 2016|
A third study, PALOMA-3, compared Ibrance in combination with Faslodex® (fulvestrant, AstraZeneca) in patients who had already progressed on endocrine therapy and also published strong positive safety and efficacy data.3 The results of this trial were the basis for Ibrance’s FDA label extension to include the treatment of patients in the second-line setting in February 2016. In all three trials, neutropenia was affected the most by the addition of Ibrance.
Since its 2015 accelerated approval, Ibrance has already gained strong utilization in the U.S. and is already the most utilized regimen as first-line therapy for postmenopausal HR+ metastatic breast cancer patients, with approximately 30% utilization.4 These strong new data will support conversion of accelerated approval in the United States and regulatory filings for Ibrance in the first-line setting elsewhere. While Ibrance currently enjoys first-in-class status (at least in the first-line setting) it may soon face more competition from two other CDK 4/6 inhibitors in this space. The first is Eli Lilly’s abemaciclib. It has two ongoing Phase III trials: MONARCH 2 (NCT02107703), which is comparing Faslodex with or without abemaciclib in 630 HR+/HER2- patients, and MONARCH 3 (NCT02246621), which is comparing the activity of non-steroidal aromatase inhibitors with or without abemaciclib in 450 HR+/HER2- patients. Abemaciclib received a boost at this year’s ASCO annual meeting with presentation of positive results from its MONARCH 1 Phase II trial. MONARCH-1 found that single-agent abemaciclib was active in refractory metastatic HR+/HER2- patients with a 19.7% objective response rate (ORR), a six-month median PFS and a 17.7-month median overall survival (OS). Toxicities were more of a concern, with diarrhea (19.7%), fatigue (12.9%), neutropenia (26.9%) and leucopenia (27.7%) being common Grade 3-4 toxicities.5 Eli Lilly’s agent had already received Breakthrough Therapy Status in October 2015. The second competitor in the first-line setting is Novartis’ ribociclib, which is being evaluated in three trials: MONALEESA-2 (NCT01958021; letrozole with or without ribociclib in 667 HR+ postmenopausal patients), MONALEESA-3 (NCT02422615; Faslodex with or without ribociclib in 660 HR+ men or postmenopausal women) and MONALEESA-7 (NCT02278120; hormone therapy with or without ribociclib in 660 premenopausal patients).
Moreover, Afinitor® (everolimus, Novartis) is currently approved for use in postmenopausal women with advanced HR+ breast cancer in combination with exemestane after relapse on letrozole or anastrozole, based on the results of the BOLERO-2 trial.6 Novartis had attempted other trials in both the first-line and relapsed settings. BOLERO-1, which evaluated Afinitor plus Herceptin and paclitaxel in HR+/HER2+ patients, failed to reach its PFS primary endpoint.7 Afinitor did meet the primary endpoint in the BOLERO-3 trial,8 which evaluated the efficacy of adding Afinitor to Herceptin and vinorelbine to Herceptin pretreated patients; however, the PFS benefit was small (HR 0.78), and Novartis has not yet filed for regulatory approval since the trial’s 2014 data publication. Other agents are being evaluated in late-stage trials for relapsed patients. These include buparlisib (PI3K inhibitor, Novartis), alpelisib (PI3Kα inhibitor, Novartis), taselisib (PI3Kα inhibitor, Genentech/Roche) and entinostat (histone deacetylase inhibitor, Syndax). If successful in the relapsed setting, these agents could also become competition to Ibrance in the first-line setting.
In spite of the future competition, Ibrance solidified its current position for use as a first-line treatment option with the results from PALOMA-2 and made it harder for competitors to dislodge its preferential status in this setting. With the extremely positive data presented at ASCO 2016, Ibrance can truly spread its wings and soar.
By: Haris Vikis, Ph.D. Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
Patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who are refractory to platinum-based therapy have a poor prognosis with a median overall survival of six months or less.1,2 While Erbitux® (cetuximab, Eli Lilly/Bristol-Myers Squibb/Merck KGaA) and platinum-based regimens are most commonly used in locally advanced and metastatic disease, immunotherapies are about to take center stage, offering significantly improved therapeutic options based on today’s findings at the American Society for Clinical Oncology (ASCO) annual meeting. Within the last two years, the PD-1 checkpoint inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo™ (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) have garnered approvals in several tumor types, including melanoma, non-small cell lung cancer, and more recently renal cell carcinoma and Hodgkin’s lymphoma for Opdivo. Data presented at ASCO 2016 now have single-agent Keytruda and Opdivo racing for approval in HNSCC.
Over the last 12 months Opdivo and Keytruda have each reported promising topline efficacy and safety data in the R/M setting for HNSCC.3-5 This prompted regulatory filing for accelerated approval for Keytruda in April 2016 based on data from the KEYNOTE-012 Phase I study.3,4 A U.S. Food and Drug Administration (FDA) action date of August 9, 2016, has been set, and it is anticipated to result in the first immunotherapy approval in HNSCC, likely subject to confirmation of the ongoing randomized Phase III KEYNOTE-040 trial. Hot on the heels of Keytruda is Opdivo, which recently reported positive data at the 2016 American Association of Cancer Research (AACR) annual meeting based on a planned interim analysis of the CHECKMATE-141 Phase III study.3 The FDA quickly granted Breakthrough Therapy designation, and a regulatory filing is highly anticipated in the near future. Given the high unmet needs within HNSCC and the enthusiasm for immunotherapy that has penetrated oncology over the last few years across multiple tumor types, these agents are likely to be approved and adopted quickly. Today at the ASCO 2016 annual meeting, four oral abstracts were presented6-9 detailing updated efficacy and safety data that strongly support the registration programs for both Keytruda and Opdivo, further prompting cross-trial comparative analyses.
Today’s presentation on CHECKMATE-141, a randomized (2:1) Phase III trial of 361 patients testing Opdivo versus investigator’s choice therapy in R/M platinum refractory patients,4 was largely a reprisal of data presented at AACR in April 2016. In the ASCO presentation, Opdivo demonstrated a median overall survival (mOS) of 7.5 months (HR: 0.70, P=0.01 when compared with the control arm). More benefit was observed in the PD-L1 ≥ 1% subgroup with a mOS of 8.7 months (HR: 0.55, 0.36-0.83) and an objective response rate (ORR) of 17%. Benefit in the PD-L1 ≤ 1% population exhibited an ORR of 12% and a mOS of 5.7 months (HR: 0.89, 0.54-1.45), which were similar to the control arm. However, as first described at AACR there is some divergence in the Kaplan-Meier curve at eight to nine months, suggesting some long-term benefit with Opdivo in this patient subgroup. Nevertheless, these data largely dismiss PD-L1 status as an effective biomarker of response, as all patients benefit regardless of PD-L1 status. The updated data presented today continue to support this. The same story holds true for HPV positivity as a biomarker of response, as both HPV-positive and HPV-negative patients continue to derive benefit. The Opdivo arm yielded superior safety. Treatment-related adverse events (TRAEs) totaled 59% (Grade 3-4 = 13%) versus 78% (35% Grade 3-4) in the control arm, and no new safety signals were reported. These data are generally consistent with the improved safety profiles in other tumor types and in the KEYNOTE trials discussed below. Finally, newly released data showed that Opdivo stabilized measures of patient-reported outcomes (PROs), while patients on investigator’s choice had declines in function and worsening of symptoms, adding another reason to support Opdivo as a new standard-of-care option in R/M HNSCC.
Merck has an aggressive development strategy for Keytruda in HNSCC, which was evident in the three abstracts reported on two Keytruda trials in the R/M setting. Long-term follow-up of expansion cohorts in HNSCC (n=192) as part of KEYNOTE-012 was presented at ASCO 2016.7 Updated data revealed an ORR that was largely maintained at 18%, with observations of significant durable responses as 85% of responses lasted six months or longer. The median OS was slightly reduced to eight months from previous reporting.3,4 A companion abstract reported in-depth biomarker analysis for PD-L1, which consistently showed increased ORR, OS and progression-free survival (PFS) in PD-L1-positive versus PD-L1-negative tumors.8 Interestingly, when tumor and inflammatory cells were included as part of a PD-L1 biomarker score, the ORR increased to 21% in PD-L1-positive versus only 6% in PD-L1 negative tumors, indicating a significantly increased ability to predict response, which may be an important consideration in the future. Biomarkers beyond PD-L1, including PD-L2 and an IFN-γ gene signature, were also strongly correlated with response, PFS and OS.
And finally newly released data from KEYNOTE-055, a large, single-arm Phase II study in platinum- and Erbitux-refractory patients, also were presented and largely confirmed the findings of KEYNOTE-012. This study was performed in a more heavily pretreated population (84% with two or more prior regimens) and reported an ORR of 17% in the total and PD-L1-positive population. TRAEs were reported at 60% (12% Grade 3-4) and agreed well with safety signals observed in the KEYNOTE-012 trial and CHECKMATE-141 trials.
How will data from these three trials be viewed in cross-trial comparisons? While the patient populations are largely similar (with the exception of the KEYNOTE-055, which was conducted in a more heavily pretreated population), the efficacy and safety data are remarkably similar between Keytruda and Opdivo (see table). Efficacy is consistently in the 18% range for ORR, two months for PFS and eight months for OS at the median. All measures of efficacy were independent of HPV status, and PD-L1 status was largely predictive of those who may benefit more but could not exclude those patients who may benefit regardless even among the PD-L1–negative population.
(≥2 prior lines)
91% had prior plat
prior plat and cetuximab
8.7 mo (PD-L1 ≥ 1%)
|8 mos||8 mos|
|mPFS||2.0 mos||2.2 mos||2.1 mos|
|ORR||17% (PD-L1 ≥ 1%)||18% (PD-L1 ≥ 1%)||17% (PD-L1 ≥ 1%)|
|Grade 3/4 TRAEs||13%||13%||12%|
Based on the filing in April, Keytruda is set to become the first immunotherapy approved for HNSCC. While Opdivo has the virtues of a larger and randomized study, Keytruda now has confirmatory evidence from the Phase II KEYNOTE-055 study, and it remains to be seen whether the data presented at ASCO are included as part of the Keytruda regulatory filing. If the FDA follows suit as it did in melanoma and lung, it will grant Keytruda accelerated approval and await data from a randomized Phase III trial (KEYNOTE-040) before granting full approval. However, Keytruda will need to compete in this setting with Opdivo, which has comparable data in a randomized Phase III trial, and durvalumab (AstraZeneca), whose ongoing EAGLE Phase III trial has yet to report. As Merck did with Keytruda, AstraZeneca has also guided for possible accelerated filings based on Phase II data.
As single-agent therapies, there is little evidence to suggest a difference between Keytruda and Opdivo PD-1/-L1 inhibitors in terms of efficacy and safety. These agents may be able to distinguish themselves by the additional development strategies being employed ‒ durvalumab and Keytruda are also exploring use of the PD-L1 biomarker to select patients; Opdivo is focusing strictly on an all-comers population; and durvalumab is also being developed in combination with tremelimumab. While refinement of biomarker populations based on PD-L1, PD-L2 and IFN-γ gene signatures have been presented, little evidence to date suggests that PD-L1 is the appropriate biomarker to distinguish responders from non-responders. Success of one PD-1 inhibitor over the other may come down to physician preference.
It is clear that single-agent Keytruda and Opdivo significantly improve the treatment armamentarium in R/M HNSCC for a patient population with limited options. Responses are durable, and the agents are well tolerated with distinct and manageable toxicity profiles. While the race for the first immunotherapy in HNSCC may be neck-and-neck, future developmental activity continues and undoubtedly is moving toward evaluation of combination therapies and integration of immunotherapy into earlier lines of therapy.
By: Len Kusdra, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
The pace of treatment in metastatic melanoma has significantly accelerated in the past couple of years. What was once a disease beset by toxic and largely ineffective treatments now enjoys a number of effective agents that have reduced the mortality of this aggressive disease. Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 antagonist, was the first of these effective immunotherapy agents that showed a significant and clinically relevant improvement in survival and led to its approval by the U.S. Food and Drug Administration (FDA) in 2011 for both first- and second-line metastatic melanoma. With the pervasive excitement of immunotherapy in the field of oncology (for which Yervoy provided proof-of-concept in melanoma), it was only a matter of time that more of these agents would make their way into melanoma. As a result, Opdivo® (nivolumab, Bristol-Myers Squibb) and Keytruda (pembrolizumab, Merck) have been added to the armamentarium for physicians in treating metastatic melanoma. The age of targeted therapy further emerged between 2012 and 2015 with approval of four agents that target the RAS-BRAF-MAPK pathway: Zelboraf® (vemurafenib, Roche/Genentech), Tafinlar® (dabrafenib, Novartis), Mekinist® (trametinib, Novartis) and Cotellic® (cobimetinib, Roche/Genentech/Exelixis, in combination with Zelboraf). All four agents are indicated for use in metastatic melanoma patients whose tumors harbor BRAF mutations.
For BRAF-mutant patients, the approval of BRAF and MEK inhibitors ushered in an era of patient segmentation and the resulting personalized medicine in melanoma; however, it is now appreciated (as is the case with other tumor types) that other mutations exist that provide niche opportunities for development of novel agents. One such mutation type is in NRAS, which occurs in about 15% of patients and is associated with more aggressive disease and poorer prognosis.1,2 Until recently, no active clinical development existed for this population, representing a major unmet need in the treatment of metastatic melanoma. This has changed with the development of binimetinib (Array Biopharma), a novel MEK inhibitor that showed promising clinical activity in a Phase II trial (NCT01320085) in patients demonstrating a 20% response rate in patients with NRAS mutations and in 20% of BRAF-mutant patients.3 Based on these promising results, Novartis decided to move binimetinib forward into late-stage development with the initiation of the NEMO clinical trial.
NEMO (NCT01763164) is an open-label, Phase III trial evaluating binimetinib versus dacarbazine in patients with advanced, unresectable (Stage IIIC) or metastatic NRAS melanoma who were either untreated or who had progressed on or after immunotherapy. Patients were randomized 2:1 to receive either 45 mg twice a day or dacarbazine at 1000 mg/m2 intravenously every three weeks. The primary endpoint is progression-free survival (PFS) with secondary endpoints including overall survival (OS), response rates, and disease control rate. In December 2015, Array Biopharma announced top-line results from NEMO demonstrating that the trial had met the primary endpoint of improving PFS (HR = 0.62, p<0.001). The median PFS for patients in the binimetinib arm was 2.8 months versus 1.5 with dacarbazine (Array BioPharma, press release, December 2015).
Today at the American Society of Clinical Oncology annual meeting, attendees were presented with more detailed findings from NEMO.3 At this interim analysis, 269 patients had received binimetinib and 133 patients had received dacarbazine. The PFS did not change from that announced in the press release, and, at this interim analysis, there was no improvement in OS (11.0 months in the binimetinib arm versus 10.1 in the dacarbazine arm); however, the data is not mature and longer-term follow-up is required before final assessment. The confirmed overall response rate was 15% (95% CI: 11% to 20%) and disease control rate was 58% (95% CI: 52%-64%) for binimetinib, respectively, compared with 7% (95% CI: 3%-13%) and 25% (18%-33%) for dacarbazine (p-value for response=0.015; p-value for the disease control rate <0.001). An intriguing piece of data arises in the prespecified subset analysis between patients who had received prior immunotherapy versus patients who had received no prior immunotherapy, although the data should be interpreted with caution given the small patient population in the prior immunotherapy arm (n=57 and 28 in the binimetinib and dacarbazine cohort, respectively). While the PFS benefit was seen in both subgroups, the benefit appeared to be greater in patients who had received prior immunotherapy (5.5 months in the binimetinib arm versus 1.6 months in the dacarbazine arm in patients who had prior immunotherapy, HR=0.46; 2.8 months in the binimetinib arm versus 1.5 months in the dacarbazine arm in patients with no prior immunotherapy). The trend favoring binimetinib in patients who had received prior immunotherapy was observed regardless of whether patients received Yervoy or a PD-1 agent. Of some concern is the side effect profile: 21% of patients discontinued treatment due to adverse events in the binimetinib group and 6% discontinued treatment in the dacarbazine arm due to side effects. Overall, binimetinib was associated with increased incidence of Grade 3/4 adverse events (68% binimetinib versus 46% dacarbazine). The most common Grade 3-4 adverse event was elevation of blood CPK (19% with binimetinib versus 0% with dacarbazine), hypertension (7% with binimetinib versus 2% with dacarbazine), and rash (4% with binimetinib versus 0% with dacarbazine).
Data from NEMO paves the way for regulatory approval of binimetinib in NRAS-mutant melanoma patients, a population with a high unmet need, making it first to market in this niche setting. While not being evaluated directly in this patient population, Keytruda, Opdivo and Yervoy may pose a competition for binimetinib. The activity seen with checkpoint inhibitors in both BRAF-mutant and BRAF-wildtype patients has raised the debate on whether to administer immunotherapy as first-line therapy in all subtypes regardless of mutational status or whether to reserve immunotherapy for the relapsed setting following failure of BRAF inhibitors in BRAF-mutant patients. Indeed, while the majority of BRAF-mutant patients will receive Zelboraf or Tafinlar with or without Mekinist, physicians also will administer Opdivo with or without Yervoy in a fraction of patients.5 With the subset analysis showing a greater efficacy benefit in patients with prior immunotherapy treatment, physicians may push binimetinib treatment to the second line, preferring to utilize immunotherapy upfront as a treatment paradigm for NRAS patients. In addition, while the PFS improvement in the entire population is significant, physicians may question the benefit-to-cost ratio given the increased rate of Grade 3/4 adverse events, thus posing a challenge to uptake. Countering that viewpoint is that NRAS patients suffer from a lack of effective clinical options, and the unmet need justifies binimetinib’s use.
Another question that inevitably arises is whether combination therapy will yield improved outcomes as seen with Tafinlar and Mekinist. As such, Array has initiated a Phase III trial evaluating binimetinib in combination with their BRAF inhibitor encorafenib (NCT01909453; COLUMBUS). This trial recently completed enrollment, and initial data readout and regulatory filing are expected to occur sometime in 2016 (Array BioPharma Investor Report, January 13, 2016).
Despite the challenges discussed, binimetinib represents the first major therapeutic option for NRAS-mutant melanoma and has offered a ray of hope in the dark muddy waters of this deadly and aggressive disease.