Update on Immunotherapeutics in the Management of Metastatic Melanoma

David Bulir, MD, PhD; Steven Liang, BHSc, PhD (Candidate); Maureen O'Malley, MD, FRCPC; Elaine McWhirter, MD, MSc


Skin Therapy Letter. 2019;24(1) 

In This Article

Combination Immunotherapy

Following the success of both CTLA-4 and PD-1 inhibitors, combination immunotherapy trials ensued. Phase I and II trials demonstrated better outcomes with combination nivolumab and ipilimumab in patients with advanced melanoma, regardless of BRAF mutation status or prior treatment, compared to monotherapy with ipilimumab. The randomized phase III CheckMate-067 trial, completed in 2015, demonstrated that patients with previously untreated malignant melanoma receiving combination ipilimumab plus nivolumab had a higher objective response rate, higher rates of complete response, and longer progression-free survival compared to monotherapy with either ipilimumab or nivolumab.[28] However, the incidence of severe (grade 3 or 4) adverse events was significantly higher among combination therapy (54%) as opposed to monotherapy with ipilimumab (24%).[28] Updated results from the CheckMate-067 trial were recently published.[29] While no change was noted in the safety profile during the 3-year period, there were significant differences in survival.[29] With a minimum of approximately 36 months of follow-up, median overall survival was 19.9 months among patients receiving ipilimumab, 37.6 months in patients receiving nivolumab, and was not reached on the combination arm.[29] Overall survival rate at 3 years had a similar pattern, with the combination group having a survival rate of 58%, and 52% and 34 % on the nivolumab and ipilimumab arms, respectively. Given the similar overall survival rate among patients receiving combination nivolumab plus ipilimumab vs. nivolumab alone, though the study was not powered for this comparison, further studies are needed to help elucidate predictors for treatment response and identify the patient population who would benefit from combination therapy vs. anti-PD-1 monotherapy. This is crucial given the significantly lower rate of toxicity with nivolumab compared to combination therapy (21% vs. 59% treatment-related grade 3–4 adverse events).[29] Recent data from a retrospective analysis of patients who discontinued combination nivolumab and ipilimumab due to adverse events during treatment induction had not reached a median overall survival, and demonstrated an objective response rate and progressionfree survival similar to patients who continued treatment.[30] Data from this study highlights the importance of identifying predictors of treatment response, and exploring treatment regimens that maximize clinical response but minimize adverse events. A recent phase Ib trial was completed in which standard dose pembrolizumab plus reduced dose ipilimumab (1 mg/kg rather than the standard 3 mg/kg) every 3 weeks for four doses, followed by pembrolizumab every 3 weeks represented a promising modified dose combination therapy with a manageable toxicity profile and anti-tumor activity.[31] Modified dose regimes are another area of clinical research needing to be explored, as few studies have looked to this area to help manage the adverse events associated with combination therapy.

Studies comparing first-line BRAF-targeted therapy to immunotherapy, with cross-over at progression, are pending results (NCT02224781). Thus, current first-line recommendations for advanced melanoma suggest either combination MEK/BRAF inhibition (in BRAF mutated patients) or immunotherapy with combination anti-PD-1/CTLA-4 or anti-PD-1 monotherapy.