The 52nd Annual Meeting of American Society of Clinical Oncology (ASCO) held in Chicago in June 3–7, 2016 provided insights on the current and emerging malignant melanoma therapies, and the treatment algorithm of unresectable and metastatic disease. Malignant melanoma is among the most dynamic indications in oncology—11 novel therapies, namely immunotherapies and targeted agents, have entered this market since 2011, providing remarkable improvements in patients’ survival. Yet, one of many prevailing questions addressed at the ASCO 2016 meeting, was how to select the patients who can benefit most from the currently available treatment options.
- Eagerly anticipated survival data for Merck & Co.’s PD-1 inhibitor Keytruda in locally advanced or metastatic malignant melanoma from the Phase I KEYNOTE-001 trial was announced at the ASCO Keytruda demonstrated PFS of 4.9 month, mOS of 24.4 months, with three-year OS of 40%, a 10% drop from the two-year analysis time-point (1). Keytruda achieved more pronounced benefit in treatment-naïve patients—three-year OS was reported in 42% patients with mOS reaching 32.2 months and PFS of 5 months. Reported responses were ongoing in 66% of all patients and 69% of treatment-naïve patients. Most importantly, CRs were durable after Keytruda discontinuation, and ongoing in 97% of patients. Presentation of Phase III KEYNOTE-006 study data demonstrated a clear superiority of Keytruda versus Bristol-Myers Squibb’s first-to-market CTLA-4 immune checkpoint inhibitor Yervoy (55% versus 43% two-year OS and PFS of 5.6 month versus 2.8 month) (2).
- The advantage of single-agent Opdivo over Yervoy was also confirmed in the CheckMate-067 study (PFS: 6.9 versus 2.9 months, ORR: 43.7% versus 19%, duration of response: 22.3 versus 14.4 months) (4). Previously, at the annual meeting of the American Association for Cancer Research (AACR) earlier this year, Opdivo achieved impressive five-year OS (34%) and mOS (20.3 months) (3).
While the superiority of first-line use of anti-PD-1 agents, Opdivo and Keytruda, over Yervoy is now confirmed, the question on the choice of treatment between anti-PD-1 monotherapy and anti- PD-1/CTLA-4 combination therapy remains unanswered. The FDA and European Commission both approved the use of Opdivo in combination with Yervoy in patients with advanced or metastatic malignant melanoma in October 2015 and May 2016, respectively. The approvals were based on the remarkable PFS and ORR data demonstrated in the CheckMate-067 and CheckMate-069 studies (5, 6). Nevertheless, the high incidence of grade 3/4 adverse effects deters the use of this highly efficacious combination regimen. Updated results of the CheckMate-067 study indicate that 56.5% of patients experienced grade 3/4 treatment-related adverse events, and 30.7% discontinued the treatment due to toxicity (4).
Improved safety and tolerability profile of anti-PD-1/CTLA-4 combination regimens is not intangible, as promising results emanate from the Phase I/II Keynote-029 study that evaluated Keytruda in combination with Yervoy. In contrast to CheckMate-067 study where Yervoy was used at the dose of 3 mg/kg, in the Keynote-029, Yervoy was administered at a 1 mg/kg dose. The results show that 1mg/kg Yervoy in combination with Keytruda (used at a standard 2 mg/kg dose), achieved impressive ORR of 57% and 15% CR. At the same time, grade 3/4 adverse effects were observed in 42% patients, leading to discontinuation of treatment in 10% of patients (7). Although a head-to-head study is needed to directly compare Opdivo + Yervoy versus Keytruda + Yervoy regimens, and the different dosing of Yervoy in these studies, it is hard not to notice that the safety and tolerability of the latter is encouraging. These results bring hope for improved safety and tolerability of immune checkpoint inhibitors combination regimens with the retained outstanding efficacy outcomes.
As noted by Prof. Georgina Long in the one the final ASCO 2016 sessions summarizing the findings from the malignant melanoma field, the survival of malignant melanoma patients has been increasing with the consecutive approvals of malignant melanoma therapies—from the approval of single-agent Yervoy in 2011, that provided 46% one-year survival rate (8), to over 70% one-year survival rate provided by BRAF/MEK and PD-1/CTLA-4 inhibitor combinations and PD-1 monotherapies. Three-year OS now reach 38% for patients treated with BRAF/MEK inhibitor combination Tafinlar + Mekinist (9), and 42% for those treated with Opdivo. As noted above, one-third of patients treated with Opdivo are still alive at the five-year mark (3). We expect that the five-year survival data for Keytruda, as well as Tafinlar + Mekinist and Zelboraf + Cotellic will be equally impressive. This outstanding breakthrough in malignant melanoma therapy brings the word ’’cure’’ closer to reality. Nevertheless, we cannot forget that while immunotherapies and targeted therapies offer increased survival benefits, some patients still do not respond to treatment. This is why we need predictive markers to select for patient populations that will respond best to therapy and to offer them the best treatment options.
New agents that are being developed for unresectable or metastatic malignant melanoma will have to demonstrate significant clinical benefit over what is being hailed as the new standard of care: PD-1 inhibitors and BRAF/MEK combination regimens. Indeed, the bar is set high. Moreover, most of the therapies currently used to treat unresectable or metastatic disease have a relatively good safety and tolerability profile, and for those which still struggle with safety and tolerability attributes (e.g., anti-PD-1/CTLA-4 inhibitor combinations), there is a lesson from the KEYNOTE-006 study—the solution could be optimal dosing. Novel therapies that can be used in conjunction with predictive biomarkers, allowing selection for high respondents and providing durable response rates will be welcomed in the malignant melanoma market.
Decision Resources Group has a finger on the pulse of the dynamic malignant melanoma market. For expert insights into market dynamics see Disease Landscape and Forecast G7 and timely primary market research on the malignant melanoma landscape see Access and Reimbursement US and Unmet Need US/EU.
- Robert C et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in Keynote-001. J Clin Oncol 34, 2016 (suppl; abstr 9503).
- Schachter J et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006. J Clin Oncol 34, 2016 (suppl; abstr 9504).
- Postow et al. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL). AACR 2016, Abstract CT002
- 4. Wolchok JD et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol 34, 2016 (suppl; abstr 9505).
5.Larkin JM. Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients with advanced melanoma (MEL) (CheckMate 067). European Journal of Cancer 51, 2015 (suppl 3, S664–S665, abstr 3303).
- Postow MA et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006-17.
- Long GV et al. Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the Keynote-029 expansion cohort. J Clin Oncol 34, 2016 (suppl; abstr 9506).
- Hodi FS et al. Improved survival with ipilimumab in patients
with metastatic melanoma. N Engl J Med 2010;363:711-23.
- Flaherty K et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: A phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. J Clin Oncol 34, 2016 (suppl; abstr 9502).