What’s new in melanoma? Combination!
© Ascierto et al. 2015
Received: 25 June 2015
Accepted: 25 June 2015
Published: 4 July 2015
Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents. New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial). Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma. Even more interesting news centered on the use of combination immunotherapy, in particular the randomized, double-blind CheckMate 067 study in which median PFS with nivolumab plus ipilimumab was 11.5 months, compared to 2.9 months with ipilimumab alone (HR 0.42) and 6.9 months with nivolumab alone (HR 0.57). Of interest, in patients with ≥5% PD-L1 expression, median PFS was 14 months with the combination or with nivolumab alone compared with 3.9 months in the ipilimumab group, while in the PD-L1 negative cohort, the combination remained superior to both monotherapies. Given that combination therapy was accompanied by a high occurrence of side-effects, this raises the suggestion that combination therapy might be reserved for PD-L1 negative patients only, with PD-L1 positive patients achieving the same benefit from nivolumab monotherapy. However, overall survival data are awaited and the equivalence of single agent to the combination remains unconvincing. Interesting data were also reported on the combination of T-VEC (talimogene laherparepvec) with ipilimumab, and the anti-PD-1 agent MEDI4736 (durvolumab) combined with dabrafenib plus trametinib. Emerging data also suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be of clinical use. In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, is no longer a just a wish for the future but is today a clinical reality with a rapidly growing evidence-base. Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.
As in recent years, melanoma was a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. If a single word could sum up this years’ melanoma news from ASCO, then “combination” would surely be the most appropriate.
Comparison of CR, ORR, PFS, DoR, and OS among the different BRAF and MEK inhibitors combination
Dabrafenib + trametinib
Vemurafenib + cobimetinib
Encorafenib + binimetinib
PD-L1 as a potential biomarker: % of PD-L1 positive patients in different clinical trials
An important consideration is that the improved PFS and ORR achieved with the combination was accompanied by a high occurrence of side-effects: 55% of patients receiving the combination had grade 3–4 events and 36.4% prematurely discontinued treatment because of its toxicity. However, over two-thirds (67.5%) of patients who discontinued treatment due to toxicities continued to respond. These data are consistent with those observed in another study of combined nivolumab and ipilimumab therapy (CheckMate 069), in which 54% of patients had grade 3–4 adverse events, leading to treatment discontinuation in 38%; 68% of these continuing to respond despite the cessation of treatment . One important characteristic of the immuno-related toxicity associated with the combination was the involvement of more than one organ, which is rare with monotherapy. However, new safety signals were not reported for the combination, with adverse events affecting the same organs as typically seen with monotherapy (i.e. the skin, gastrointestinal tract, liver, endocrine system, lungs). Moreover, these toxicities were manageable using the established algorithm for the treatment of the immuno-related adverse events. Importantly, even in this large multi-national study in which many investigators had not previously used the combination regimen, there were no treatment-related deaths. It should also be noted that these side effects are primarily related to ipilimumab and similar levels of side effects were seen in studies using a high dose of ipilimumab, e.g. the phase III study of first-line combined dacarbazine plus ipilimumab 10 mg/kg (50% grade 3–4 AEs)  and in the EORTC adjuvant trial with high-dosage ipilimumab (40.5%) .
Another combined immunotherapeutic approach was the combination of T-VEC (talimogene laherparepvec), an oncolytic virus which includes a gene that encodes for GM-CSF, with ipilimumab . These were an update of data presented at ASCO in 2014 and, in the 18 patients enrolled to date, ORR was 56% and median (PFS) was 10.6 months. Median OS was not reached; 12- and 18-month survival were 72.2 and 67%.
That targeted therapy has an important effect on the immune system is well known and the possibility of combining a BRAF or MEK inhibitor with immunotherapy is an interesting approach. However, phase I data showed that combined vemurafenib and ipilimumab increases liver toxicity (although this was not reported with dabrafenib plus ipilimumab) , while the triple combination of ipilimumab plus dabrafenib and trametinib has reported to increase the risk of bowel perforation. The development of anti-PD-1/PD-L1 agents which are more potent and less toxic than ipilimumab means the possibility of a combined approach with a BRAF or MEK inhibitor is more realistic. An interesting phase I study reported data on the combination of the anti-PD-L1 antibody, MEDI4736 (durvolumab) with dabrafenib plus trametinib in patients with stage IIIc/IV melanoma . Patients were enrolled by BRAF status into three different cohorts; BRAF-mutant patients received the triple combination and BRAF wild-type (WT) patients received durvolumab plus trametinib or sequential trametinib then durvolumab. Treatment with the triple combination resulted in an ORR of 69%, and DCR of 100%. In the BRAF WT cohorts, ORR was 21% and DCR was 79% in the combination group, while in the sequential group ORR was 13%, and DCR was 80%; however, data for the sequential group data could be affected by the short-term follow up. Most importantly, these combinations had a manageable safety profile. Despite these promising results, longer follow-up will be necessary to determine the contribution of durvolumab to the impressive activity seen with the triple drug combination.
Finally, emerging data have suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be more meaningful than PD-L1. The interferon-γ signature 10 gene (related to inflammation) seemed to correlate with a better outcome in patients receiving the anti-PD-1 agent, pembrolizumab, both in terms of PFS and OS . Similarly, although not in melanoma patients, data from a phase I study of patients with renal cell cancer reported that baseline upregulation of genes known to be upregulated by ipilimumab in melanoma, together with other immunorelated genes, was strongly correlated with the outcome . Another important finding was the strong correlation between deficiency in the mismatch repair and the response to immunotherapy that was evidenced in colorectal and other solid cancers and is likely to be a major focus of interest in the future .
In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, are no longer a just a wish for the future  but are today a clinical reality with a rapidly growing evidence-base. Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.
PAA, FMM, and MBA drafted the final manuscript. All authors read and approved the final manuscript.
Compliance with ethical guidelines
Competing interests PAA has/had consultant and advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche-Genenetech, Ventana Medical Systems, Novartis, and Amgen. He received research fund from Bristol Myers Squibb, Roche-Genentech, and Ventana. FMM has no conflict of interest to declare. MBA has/had consultant and advisory roles for Bristol Myers Squibb, Merck Sharp & Dohme, Roche-Genentech, Novartis, Amgen, Glaxo Smith Kline, NeoStem and Pfizer.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M et al (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867–1876PubMedView ArticleGoogle Scholar
- Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J et al (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877–1888PubMedView ArticleGoogle Scholar
- Larkin JMG, Yan Y, McArthur GA, Ascierto PA, Liszkay G, Maio M et al (2015) Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol 33 (suppl; abstr 9006)Google Scholar
- Long GV, Stroyakovskiy D, Gogas H, Levchenko E, De Braud FG, Larkin JMG, et al (2015) Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. J Clin Oncol 33 (suppl; abstr 102)Google Scholar
- Flaherty K, Daud A, Weber JS, Sosman JA, Kim K, Gonzalez R et al (2014) Updated overall survival (OS) for BRF113220, a phase 1–2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D + T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM). J Clin Oncol 32:5s (suppl; abstr 9010^)Google Scholar
- Sullivan RJ, Weber JS, Patel SP, Dummer R, Miller WH, Cosgrove D et al (2015) A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. J Clin Oncol 33 (suppl; abstr 9007)Google Scholar
- Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med [Epub ahead of print]Google Scholar
- Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006–2017PubMedView ArticleGoogle Scholar
- Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526PubMedView ArticleGoogle Scholar
- Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H et al (2015) Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16:522–530PubMedView ArticleGoogle Scholar
- Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454PubMed CentralPubMedView ArticleGoogle Scholar
- Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133PubMedView ArticleGoogle Scholar
- Chapman PB, D’Angelo SP, Wolchok JD (2015) Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N Engl J Med 372:2073–2074PubMedView ArticleGoogle Scholar
- Puzanov I, Milhem MM, Andtbacka RHI, Minor DR, Hamid O, Li A et al (2015) Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin Oncol 33 (suppl; abstr 9063)Google Scholar
- Puzanov I, Callahan MK, Linette GP, Patel SP, Luke JL, Sosman JA et al (2014) Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM). J Clin Oncol 32:5s (suppl; abstr 2511)Google Scholar
- Ribas A, Butler M, Lutzky J, Lawrence DP, Robert C, Miller W et al (2015) Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol 33 (suppl; abstr 3003)Google Scholar
- Ribas A, Robert C, Hodi FS, Wolchok JD, Joshua AM, Hwu W-J et al (2015) Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. J Clin Oncol 33 (suppl; abstr 3001)Google Scholar
- Choueiri TK, Fishman MN, Escudier B, McDermott DF, Kluger HM, Stadler WM et al (2015) Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma (mRCC): association of biomarkers with clinical outcomes. J Clin Oncol 33 (suppl; abstr 4500)Google Scholar
- Le DT, Uram JE, Wang H, Bartlett B, Kemberling H, Eyring A et al (2015) PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol 33 (suppl; abstr LBA100)Google Scholar
- Ascierto PA, Streicher HZ, Sznol M (2010) Melanoma: a model for testing new agents in combination therapies. J Transl Med 8:38PubMed CentralPubMedView ArticleGoogle Scholar
- Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384PubMedView ArticleGoogle Scholar
- Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330PubMedView ArticleGoogle Scholar
- Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532Google Scholar
- Puzanov I, Dummer R, Schachter J, Pavlick AC, Gonzalez R, Ascierto PA et al (2015) Efficacy based on tumor PD-L1 expression in KEYNOTE-002, a randomized comparison of pembrolizumab (pembro; MK-3475) versus chemotherapy in patients (pts) with ipilimumab-refractory (IPI-R) advanced melanoma (MEL). J Clin Oncol 33 (suppl; abstr 3012)Google Scholar
- Joseph R, Elassaiss-Schaap J, Wolchok JD, Joshua AM, Ribas A, Hodi FS et al (2014) Baseline tumor size (BTS) and PD-L1 expression are independently associated with clinical outcomes in patients (pts) with metastatic melanoma (MM) treated with pembrolizumab (pembro; MK-3475). Pigment Cell Melanoma Res 27;1169:1188 (abstract)Google Scholar