A vast array of study results on melanoma were presented by Piotr Rutkowski, from the Maria Skłodowska-Curie Institute of Oncology, Warsaw, Poland, during a highlight session at the ESMO Congress 2019.
Stage III melanoma is a heterogeneous disease for which adjuvant therapy is now established, based on the results of large studies such as COMBI-AD, CheckMate-238 or KEYNOTE 054. Data on 3-year efficacy and biomarkers from the CheckMate 238 Phase 3 study were presented1. The randomized study compared nivolumab (n = 453) and ipilimumab (n = 453) in adjuvant therapy in patients with resected high-risk stage III/IV melanoma. After 24 months, 63% of patients under nivolumab and 50% of patients under ipilimumab survived without relapse, after 36 months it was 58% under nivolumab and 45% under ipilimumab. The more beneficial effect of nivolumab, therefore, continued over time. However, a number of questions remain, e.g. whether there is a plateau of the recurrence-free survival (RFS) curve and whether overall survival with nivolumab is also better. There is also the question of how patients should be treated after a relapse.
The working group led by Dirk Schadendorf in Essen, Germany, presented the IMMUNED study at ESMO. In the double-blind, randomized phase 2 study they compared the efficacy of nivolumab alone (n = 59) and of nivolumab plus ipilimumab (n = 56) with placebo (n = 52) in the adjuvant therapy of stage IV melanomas under no signs of disease (NED) after resection and radiation2. The primary endpoint was RFS. After a median follow-up of 28.4 months, RFS was not achieved in the combination group, 12.4 months in the nivolumab group and 6.4 months in the placebo group. The hazard ratio was 0.23 for the comparison of combination vs placebo and 0.56 for the comparison of monotherapy vs placebo. The effect was particularly pronounced in BRAF-mutated melanomas, which Rutkowski sees as further evidence that aggressive therapy with the combination makes sense in these cases. However, this is brought with increased serious side effects. 70.9% of the patients in the combination group suffered an adverse effect of grade 3/4. Confirmation of the data is expected with the CheckMate 915 study.
A randomized, open-label, multicenter Phase-2 study compared the efficacy and tolerability of talimogen laherparepvec (T-VEC) with subsequent surgery (n = 75) or surgery alone (n = 75) in patients with stage IIIB-IVM1a resectable melanoma3. The primary endpoint was RFS after 2 years. This was 50.5% in the T-VEC group and 30.2% in the surgery group (HR 0.66, p = 0.038). Overall survival after 2 years was also better in the T-VEC group with 88.9% than in the surgery group with 77.4% (HR 0.49, p = 0.05). There were also signals for pathological complete response (pCR) because 9 out of the 13 patients with pCR had no recurrence at the time of analysis. Rutkowski emphasized that this is the first and largest randomized study to date on neoadjuvant therapy in this patient group. In the T-VEC arm, no Grade 5 side effects and no unexpected reactions occurred.
The 3-year data from the OPACIN study showed that neoadjuvant therapy with ipilimumab plus nivolumab in macroscopic stage-III melanoma had increased the 3-year RFS from 60% to 80% for surgery alone and the 3-year OS from 70 to 90%4. After a median follow-up of 36.7 months, no patient and no patient with pCR had relapsed. This indicates that pCR may serve as a surrogate marker for RFS and OS in studies investigating neoadjuvant therapy with checkpoint inhibitors.
According to the data now available from large studies, the 5-year survival rate for advanced metastatic melanoma is between 34 and 52%. Recent data from the CheckMate-067 study showed that 52% survival rates with nivolumab/ipilimumab after 5 years were still better than with nivolumab alone (44%) or ipilimumab alone (26%)5,6. The median OS has not yet been reached for the combination. This makes it the only therapy for metastatic melanoma that achieves the median survival of more than 5 years.
PFS was also better with 36% vs 29% and 8%, respectively. According to Rutkowski, it is important that we now see a plateau in PFS. After 5 years, 74% of patients in the nivolumab/ipilimumab group are still alive and do not need therapy, 58% in the nivolumab group and 45% in the ipilimumab group.
The combination of cobimetinib and atezolizumab (n= 222) was compared in the IMspire 170 study with pembrolizumab (n= 224) in untreated patients with advanced wild-type BRAFV600 melanoma7. However, the study did not meet the primary endpoint of PFS. Side effects were more common with the combination than with pembrolizumab.
Brain metastases are common in melanoma patients and occur in 20 to 25% of patients diagnosed with stage IV melanoma. During an autopsy, they can be detected in 50 to 70% of cases. Systemic therapies work, but the effect does not last long. In the ABC Phase-2 study, asymptomatic melanoma patients without pre-treatment were randomly treated with brain metastases with nivolumab/ipilimumab (n = 35) or nivolumab (n = 25), another 16 pre-treated patients with symptoms received nivolumab8. The intracranial response was significantly higher with 51% under the combination than with 20% under monotherapy. The median intracranial PFS was 5.4 and 2.5 months, respectively. According to Rutkowski, the data support the use of nivolumab ± ipilimumab in melanoma patients with brain metastases, especially when they require less than 10 mg prednisone.
1. Weber J, et al. adjuvant nivolumab versus ipilimumab in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase III CheckMate 238 trial. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 1310O.
2. Schadendorf D, et al. adjuvant immunotherapy with nivolumab alone or in combination with ipilimumab versus placebo in stage IV melanoma patients with no evidence of disease (NED): A randomized, double-blind phase II trial (IMMUNED). ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA67.
3. Dummer R, et al. Primary 2-year results of a phase II, multicenter, randomized, open-label trial of efficacy and safety for talimogene laherparepvec (T-VEC) neoadjuvant treatment plus surgery vs surg in patients with resectable stage IIIB-IVM1a melanoma. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA66.
4. Blank CU, et al. 3-year relapse-free survival, overall survival and long-term toxicity of (neo)adjuvant ipilimumab + nivolumab in macroscopic stage III melanoma (OpACIN trial). ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 1313PD.
5. Larkin J, et al. 5-year survival outcomes of the CheckMate 067 phase III trial of nivolumab plus ipilimumab combination therapy in advanced melanoma. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA68_PR.
6. Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019, published online on 28 September 2019.
7. Arance A, et al. combination treatment with cobimetinib and atezolizumab vs. pembrolizumab in previously untreated patients with BRAFV600 wild type advanced melanoma: Primary analysis from the phase III IMspire170 trial. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA69.
8. Long GV, et al. Long-term outcomes from the randomized phase II study of nivolumab or nivo+ipilimumab in patients with melanoma brain metastases: Anti-PD1 brain collaboration (ABC). ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 1311O.