By: Arnold DuBell, Ph.D., M.B.A, Consultant, Clinical and Scientific Assessment, Kantar Health and Greg Wolfe, Ph.D., Senior Consultant, Clinical and Scientific Assessment, Kantar Health
Recent progress in the development of novel therapeutic agents to combat melanoma has been tremendous. Immune checkpoint inhibition and targeted inhibition of BRAF and MEK are two therapeutic approaches that have significantly improved survival for patients with advanced melanoma. Since 2011, the Food and Drug Administration (FDA) has approved three checkpoint inhibitors: starting with the CTLA4 inhibitor Yervoy® (ipilimumab, Bristol-Myers Squibb), with subsequent approvals of PD-1 inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo® (nivolumab, Ono/Bristol-Myers Squibb).
Immune checkpoints play critical roles in balancing co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T-cell responses. PD-1 is a key immune checkpoint receptor expressed on activated T-cells. Binding of PD-1 to its ligand (PD-L1) results in suppression of the immune response, and tumor cells can manipulate this critical pathway to elude attack by tumor-infiltrating T-cells.
Opdivo holds the title of the first PD-1 inhibitor to gain global regulatory approval when it was approved in Japan in July 2014 for melanoma. In September 2014, Keytruda became the first PD-1 inhibitor to gain approval in the U.S. when the FDA awarded Keytruda accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. However, the race to the U.S. market was tight as Opdivo received accelerated approval from the FDA in December 2014 for a similar indication. Although both Keytruda and Opdivo were approved for previously treated melanoma, the National Comprehensive Cancer Network (NCCN) was sufficiently convinced by these agents’ activity in pretreated patients that the latest guidelines (v3.2015) recommend consideration of use of both Opdivo and Keytruda instead of Yervoy in the first-line setting. With the battle now shifting to treatment-naïve advanced melanoma, these agents need to prove their superiority to Yervoy, which has ruled as the only approved checkpoint inhibitor in the U.S. since 2011.
Results from the Phase III KEYNOTE-006 trial (NCT01866319) were presented Sunday at the AACR (American Association of Cancer Research) Annual Meeting in Philadelphia.1 Merck initiated this pivotal, three-arm trial in August 2013 to evaluate the safety and efficacy of two dosing schedules of Keytruda compared to Yervoy for the treatment of Yervoy-naïve patients with unresectable or metastatic melanoma. In this study 834 unresectable, Stage III/IV patients were randomized (1:1:1) to receive Keytruda (10 mg IV) either once every two weeks (Q2W) or once every three weeks (Q3W) for up to two years or Yervoy (3 mg/kg IV) once Q3W for a total of four doses (the approved Yervoy dose regimen). Eligible patients may have received one or fewer prior therapy excluding anti-CTLA4, PD-1 and PD-L1 agents; one-third of enrolled patients had received prior therapy, typically chemotherapy or a BRAF inhibitor (one-third of enrolled patients had BRAF mutations). Progression-free survival (PFS) and overall survival (OS) were co-primary endpoints.
Keytruda was superior to Yervoy in all key study endpoints. Median PFS was 5.5 months for Keytruda (Q2W), 4.1 months for Keytruda (Q3W), and 2.8 months for Yervoy; PFS rates at six months were 47.3% for Keytruda (Q2W) (HR= 0.58; p<0.00001), 46.4% for Keytruda (Q3W) (0.58; p=0.00001), and 26.5% for Yervoy. Median OS data was immature for all study arms, while the OS rates at 12 months were 74.1% for Keytruda (Q2W) (HR= 0.63; p<0.00052), 68.4% for Keytruda (Q3W) (0.69; p=0.00358), and 58.2% for Yervoy. Overall response rates (ORR) were 33.7% for Keytruda (Q2W) and 32.9% for Keytruda (Q3W), versus 11.9% for Yervoy. Keytruda also demonstrated a superior safety profile compared with Yervoy. Grade 3 to 5 adverse events attributable to study drugs were reported in 13.2% (Keytruda Q2W), 10.1% (Keytruda Q3W), and 19.9% (Yervoy) of patients with events similar to what is characteristic of the class but with individual adverse events occurring rarely; rates of treatment discontinuation due to treatment-related adverse events were 4.0%, 6.9%, and 9.4%, respectively. As OS results at the second interim analysis crossed the prespecified efficacy boundary, the KEYNOTE-006 trial was halted early and results were unblinded; however, the study is ongoing for safety and survival follow-up until the final analysis.
Compared with patients randomized to Yervoy, patients randomized to Keytruda experienced a 1.8-fold improvement in the six-month PFS rate, a reduction in risk of death of 31% to 37%, and a 2.8-fold increase in ORR. With such strongly positive results from KEYNOTE-006 in hand, Merck will move toward regulatory filing of Keytruda in the first-line setting as quickly as possible. As Keytruda demonstrated significant improvement in both PFS and OS compared with Yervoy, it is evident that Yervoy’s dominance as front-line standard of care for BRAF-wildtype patients will soon fade away as PD-1 checkpoint inhibitors assume this role.
The question remains as to which PD-1 inhibitor will win the battle for the front-line setting. Although the results from KEYNOTE-006 are outstanding, one must not forget that in June 2014 Bristol-Myers Squibb announced preliminary results of their Phase III CheckMate-066 trial (NCT01721772) that evaluated Opdivo versus dacarbazine as first-line therapy in 418 patients with unresectable Stage III or Stage IV melanoma. CheckMate-066 was prematurely terminated because the independent data-monitoring committee confirmed a significant OS benefit was achieved (BMS press release, June 25, 2014). Median OS was not reached for the Opdivo arm and was 10.8 months for the dacarbazine arm (p=<0.001). One-year survival was 73% for Opdivo-treated patients versus 42% for dacarbazine (p<0.0001); median PFS was 5.1 months for the Opdivo arm versus 2.2 months for dacarbazine; and objective response rates were 40.0% versus 13.9% for Opdivo and dacarbazine, respectively.2 Drug-related Grade 3/4 adverse events occurred in 12% of patients treated with Opdivo and 18% of patients treated with dacarbazine, with only 2% and 3% of patients, respectively, discontinuing due to adverse event. If one indulges in a cross-trial comparison (with all of the usual caveats) with regard to PFS, OS and ORR, Keytruda and Opdivo appear to have quite similar efficacies and safety profiles as front-line agents for advanced/metastatic melanoma. With the activity of Keytruda and Opdivo appearing so similar, how will physicians choose between two highly active agents? Although Opdivo was the first to report results of the first-line randomized trial, it was in comparison with a now-defunct standard of care (dacarbazine). Keytruda may be at an advantage in having shown clear superiority against the current standard of care, Yervoy. That could propel physicians to preferentially utilize Keytruda. However, it should not be overlooked that the dose of Keytruda utilized in the KEYNOTE-006 trial (10 mg/kg Q2W or Q3W) is significantly higher than the dose at which it is currently approved (and priced) in the relapsed/refractory setting (2 mg/kg Q2W). At the currently approved dose, Keytruda costs $12,500 per month; at the dose tested in the KEYNOTE-006 trial, the monthly price for Keytruda would presumably be in excess of $60,000 per month. Clearly this is not sustainable, so cost of therapy could become a major decision factor when choosing between Keytruda and Opdivo (at the dose tested in CheckMate-066 and -067, the cost per month is $12,500), unless the pricing of the higher dose of Keytruda is creatively managed.
Bristol-Myers Squibb is not far behind with its own trial comparing Opdivo with Yervoy. The company is conducting the Phase III CheckMate-067 trial (NCT01844505) to determine whether Opdivo alone or Opdivo in combination with Yervoy will extend survival compared with Yervoy alone in patients with previously untreated metastatic melanoma. OS and PFS are co-primary endpoints. Given the results of KEYNOTE-006, one would expect that Opdivo also will be able to best Yervoy when comparing the two monotherapies. CheckMate-067 will confirm these expectations, but perhaps more importantly will inform how efficacy of the combination of inhibition of PD-1 and CTLA4 checkpoint pathways compares to a PD-1 inhibitor alone. What level of gain in survival can be expected with this dual-blockade? Will toxicity of the combined agents be insurmountable?
Between the CheckMate-066 results first reported at the Society of Melanoma Research in November 2014, the KEYNOTE-006 results reported at AACR in April 2015, and looking ahead to the widely anticipated CheckMate-067 trial readout, a heated battle is playing out among the checkpoint inhibitors in advanced melanoma. With both PD-1 inhibitors showing one-year overall survival in excess of 70%, compared with less than 40% one-year survival historically,3 this battle is turning into a win-win for patients and physicians.
1. Ribas A, Schachter J, Long GV et al. Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma. AACT Abstract CT101, 2015.
2. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Eng J Med. 2014;372:320-330.
3. Kantar Health, CancerMPact® Patient Metrics U.S., accessed April 19, 2015.
Final progression-free survival (PFS) data from the PALOMA-1 phase II trial was presented at the Plenary Session of the 2014 American Association for Cancer Research (AACR; Finn, abstract CT-101). Observers were expecting positive news, since interim analyses already had shown PFS benefit for palbociclib (PD 0332991, Pfizer/Amgen/Onyx) and Pfizer had indicated via press release that the final PFS results were positive (February 3, 2014). However, the big question wasn’t whether the data would be positive, it was whether the final data would be good enough to support filing for accelerated approval.
PALOMA-1 (NCT00721409) was an open label trial that randomized 165 patients to letrozole or letrozole plus palbociclib. As part of the trial design, both CCND-1 amplification or p16 loss were prospectively evaluated as biomarkers, but only ER-status was predictive of activity (Finn, Abstract 100O, IMPAKT 2012). An interim analysis based on 61 events presented at the San Antonio Breast Cancer Symposium (SABCS) in 2012 demonstrated a striking 18.6 month improvement in PFS when palbociclib was added to letrozole (26.1 months versus 7.5 months, HR 0.37, p<0.001; Finn, Abstract S1-6).
The final analysis consisted of 100 PFS events, and palbociclib maintained the impressive PFS benefit (20.2 months versus 10.2 months, HR 0.488, p=0.0004). All evaluated subgroups showed a strong benefit for palbociclib. Palbociclib plus letrozole also increased objective response rate (ORR; 43% versus 33%; primarily partial responses) and clinical benefit rate (81% versus 56%). The presenter suggested that the lower response rate could be attributed to fact that PALOMA-1 included patients with bone metastases that cannot be easily assessed for response. Further efficacy analysis conducted in patients with measurable disease (n=65 in palbociclib arm and n=66 in letrozole arm) demonstrated an ORR of 55% versus 39%. Preliminary analysis on overall survival (OS) indicates only a trend to an OS benefit: 37.5 months versus 33.3 months, HR 0.813, 0.2105). The toxicity profile for palbociclib was manageable given that the relative dose intensity was 94% and the discontinuation rate due to adverse events (AEs) was 13% in palbociclib plus letrozole versus 2% in letrozole alone arm. Common Grade 3/4 toxicities in palbociclib plus letrozole versus letrozole alone arm included neutropenia (54% versus 1%), leucopenia (19% versus 0%), fatigue (4% versus 1%) and anemia (6% versus 1%).
The impressive PFS benefit was definitely well received by those in attendance at the conference. The discussant (Dr. Jose Baselga) stated “these results are strikingly positive and with a large potential impact to patients with ER+ breast cancer.” The important question remains: what will Pfizer do with these data? Palbociclib was awarded “breakthrough therapy” designation in April 2013 based on the interim data from PALOMA-1. Moreover, historical data presented by Dr. Finn suggest that the PFS benefit for palbociclib compares favorably: past trials showed that aromatase inhibitor treatment was associated with a 10-13 month PFS benefit.
Historically in breast cancer, overall survival has been a major criteria for approval by the U.S. Food and Drug Administration especially given the narrow PFS benefit observed with some agents in this disease. Based on the immature OS results from PALOMA-1, it is unclear if palbociclib will be able to achieve a significant survival advantage. The discussant Dr. Baselga noted caution on accepting the PFS benefits from Phase II data based on recent failures with most recent example of iniparib that failed in Phase III trials following impressive Phase II benefit. Given the small sample size and the aggressive nature of breast cancer, it might be ideal to await the results of ongoing Phase III PALOMA-2 study (NCT01740427) of palbociclib plus letrozole as first-line therapy or the Phase III PALOMA-3 study (NCT01942135), which is comparing the addition of palbociclib to faslodex in later lines of therapy.
Dr. Baselga acknowledged the difficulty for Pfizer as they make this this decision, when he noted some of the competition for palbociclib. Eli Lilly’s CDK 4/6 inhibitor bemaciclib (LY2835219) recently presented phase I data in breast cancer patients, and will be examined in a phase II trial in HR+, HER2- patients (NCT02102490). Also, Novartis has recently reported Phase I data for their CDK 4/6 inhibitor LEE011 (Infante, 2014 International Congress on Targeted Anticancer Therapies) that was evaluated in a dose-escalation study in 78 patients with solid tumors. Although the trial had only five breast cancer patients, LEE011 as a monotherapy achieved two partial responses and was well-tolerated. This phase I data supported Novartis’ Phase III trial (MONALEESA-2; CLEE011A2301; NCT01958021) which will evaluate the efficacy of LEE011 in combination with letrozole. Finally, Novaris’s PI3K inhibitor buparlisib (BKM120) is the subject of two phase III trials [BELLE-2 (NCT01610284); BELLE-3 (NCT01633060)] for HER2-positive patients. This competition highlights Pfizer’s quandary. If they choose (or the FDA forces them to choose) to wait, they stand a chance of losing their first-to-market advantage. However, it is also hard to ignore such a striking PFS benefit in this patient population. After all, Afinitor® (everolimus, Novartis) was approved in the relapsed/refractory HER2- postmenopausal setting based on a 6-month PFS benefit.
No matter what happens next for now, it seems CDK inhibitors have gained a slot in physician’s arsenal of options for the treatment of HR+ metastatic breast cancer. Kantar Health eagerly awaits to hear Pfizer’s future plans for palbociclib.
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by Neesha Suvarna, Ph.D., Consultant, Kantar Health and Arnold DuBell, Ph.D., M.B.A., Consultant, Kantar Health
On Sunday at the American Association for Cancer Research (AACR) 2013 annual meeting, Jose Baselga, M.D., Ph.D., physician-in-chief at the Memorial Sloan-Kettering Cancer Center, presented new data from the Phase III EMILIA trial (Abstract LB-63) that suggested a relationship between tumor biomarkers and efficacy of Kadcyla® (TDM-1, ado-trastuzumab emtansine; Roche/Genentech). Kadcyla is a novel antibody-drug conjugate that comprises a potent microtubule polymerization inhibitor conjugated to the Herceptin® (trastuzumab; Roche / Genentech) monoclonal antibody via a highly stable linker. Kadcyla is designed to take advantage of the targeted nature of the antibody to selectively deliver the cytotoxic agent to HER2+ breast cancer cells. The EMILIA trial evaluated Kadcyla monotherapy versus Xeloda® (capecitabine, Roche) plus Tykerb® (lapatinib, GlaxoSmithKline) (XT) in relapsed HER2+ metastatic breast cancer patients. The positive results led to its regulatory approval in the United States in February 2013. Roche’s Herceptin, currently dominates the HER2+ market, with about 85% utilization in front-line HER2+ metastatic breast cancer patients. Although Tykerb is approved in the second-line in combination with Xeloda, about half of U.S. patients are rechallenged with Herceptin plus chemotherapy, leaving Tykerb for later-lines of therapy.
Baselga and colleagues conducted a biomarker analysis as part of the EMILIA study to determine whether variable expression of HER2, HER3, EGFR, PTEN and mutational status of PIK3CA gene impact efficacy of Kadcyla or Tykerb plus Xeloda. Patients in both treatment arms were evaluated according to intratumoral HER2 mRNA levels (at least median HER2 mRNA level versus less than median HER2 mRNA level). Patients with tumors expressing higher levels of HER2 mRNA (median or higher) derived greater overall survival benefit from Kadcyla (34.1 months) versus patients with tumors expressing lower levels of HER2 (26.5 months). In contrast, there was no difference in overall survival benefit in patients treated with Tykerb/Xeloda when stratified by HER2 mRNA levels (24.8 months for high levels versus 23.7 months for low levels). Similar analysis based on mRNA expression levels of HER3, EGFR and PTEN revealed no relationship between these biomarkers and efficacies of Kadcyla or Tykerb/Xeloda regimens. However, the mutational status of PIK3CA was discovered to be associated with improved outcomes when treated with Kadcyla but not Tykerb/Xeloda.
The PIK3CA gene encodes the alpha isoform of PI3K catalytic subunit, which is frequently mutated in HER2+ breast cancers and is thought to represent one of the resistance mechanisms to HER2-targeted therapy. PIK3CA-activating mutations may impact efficacy of anti-HER2 therapies as PIK3CA lies downstream from HER2 in the signal transduction pathway. Therefore, efficacies of these regimens were examined in patients according to PIK3CA-activating mutational status. Indeed, for patients in the Tykerb/Xeloda arm, overall survival of patients with PIK3CA activating mutations was worse compared to patients with PIK3CA wild-type tumors (17.3 versus 27.8 months). In contrast, overall survival appeared unaffected by PIK3CA mutational status in patients in the Kadcyla arm: in patients with mutated PIK3CA Kadcyla improved median progression-free survival (mPFS) from 4.3 months to 10.9 months, and in patients with wild-type PIK3CA Kadcyla improved mPFS from 6.4 to 9.8 months. These data suggest that Kadcyla may be able to bypass a common HER2 resistance pathway that has confounded anti-HER2 therapies and offers a new treatment option to women who would have otherwise not fared as well from other HER2-targeted therapies. Prior data has suggested no significant association between PIK3CA mutation and Herceptin efficacy, similar to what is observed here for Kadcyla, suggesting that this resistance mechanism may primarily have implications for use of Tykerb or other HER2 family tyrosine kinase inhibitors.
These results are thought-provoking and set the stage for future biomarker-driven analyses to guide choice of therapy upon relapse, although it’s premature to begin integrating into clinical practice at this time. However, these data could support tighter definitions of patients eligible for therapy with these agents, possibly by raising the threshold for HER2 positivity or by using PIK3CA status to help physicians make an informed decision on whether Tykerb or Kadcyla is a better second-line option for individual patients. The field has grown adept at incorporating biomarker analyses into initial patient diagnosis to guide treatment algorithms, but we are only beginning to understand the potential importance of re-testing patients throughout the progression of disease to further optimize and individualize care.
By: Stephanie Hawthorne, PhD, Director, Kantar Health; Tatiana Spicakova, PhD, Consultant, Kantar Health; and Greg Wolfe, PhD, Senior Consultant, Kantar Health