Experts provided information on the current status of combination immunotherapy, adjuvant immune checkpoint blockade and long-term survival after PD-1 inhibitor therapy in the course of two satellite symposia at the German Skin Cancer Congress.
The long-term survival rates achievable by dual immune checkpoint blockade with nivolumab and ipilimumab in patients with metastatic or non-resectable melanoma are impressive. Adjuvant treatment with nivolumab achieves more efficacy with fewer side effects compared with ipilimumab. The chances of remaining tumor-free in the long term are significantly increased by adjuvant nivolumab. 4- and even 5-year long-term data demonstrate durable antitumor efficacy in many patients who have responded to treatment with pembrolizumab.
Higher long-term survival with combination immunotherapy
The effect of immunotherapy for malignant melanoma can be increased when two checkpoint inhibitors with different targets are used in combination. The CTLA-4 antibody ipilimumab (Yervoy®) abrogates the shutdown of T cell activity achieved via the immune checkpoint CTLA-4 in the priming phase of T cell activation in lymph nodes. PD-1 antibodies such as nivolumab (Opdivo®), on the other hand, can reactivate T-cell activity in tumor tissue in the effector phase, which is switched off via the immune checkpoint PD-1. Dual checkpoint blockade with nivolumab plus ipilimumab was compared with the two monotherapies in the randomized double-blind phase III Check-Mate 067 trial. The study enrolled 945 patients with metastatic or non-resectable malignant melanoma. Ipilimumab was treated for three months – four cycles every three weeks. Patients in the combination therapy arm received additional nivolumab during the four cycles, then nivolumab monotherapy every two weeks. After three years, progression-free survival was achieved in 10% with ipilimumab monotherapy, 32% with nivolumab monotherapy, and 39% with combination therapy [1]. The rates of 3-year overall survival were 34% and 52% and 58%, respectively [1]. After three years, no follow-up therapy was needed by 20% and 45% and 59% of patients, respectively [1].
The safety profile of the combination therapy has been consistent with previous studies, said Prof. Dirk Schadendorf, MD, Essen, Germany. Patients who discontinue treatment due to side effects may also benefit from combination therapy. This was the result of a pooled analysis of randomized phase II/III trials. Overall survival was comparable at 18 months in treatment discontinuers and patients without treatment discontinuation, respectively (67% vs. 62%) [2].
Successful adjuvant monotherapy with nivolumab
Checkpoint inhibition is about to move into the adjuvant setting of melanoma therapy, reported Prof. Ralf Gutzmer, MD, Hannover. Despite complete removal of tumor tissue, invisible micrometastases remaining in the body can cause recurrence. Therefore, it was necessary to determine whether immunotherapies are suitable for the elimination of microscopic tumor remnants. In the EORTC-18071 trial, adjuvant ipilimumab therapy was shown to be beneficial compared with placebo in stage III patients after complete resection in terms of relapse-free and overall survival. The randomized double-blind phase III Check-Mate 238 trial evaluated adjuvant nivolumab therapy compared with adjuvant ipilimumab therapy. The study enrolled 906 patients in stages IIIB, IIIC, or IV after complete resection of regional lymph node metastases or distant metastases [3]. With a treatment duration of up to one year, half of the patients received nivolumab 3 mg per kg infused intravenously every two weeks and the other half received high-dose ipilimumab (for induction 10 mg per kg four times every three weeks, then one infusion every twelve weeks in the maintenance phase). Nivolumab therapy achieved significant improvement in relapse-free survival. At 12 months, the relapse-free survival rate was 70.5% (vs. 60.8% in the ipilimumab group), at 18 months 66.4% (vs. 52.7%) [3], and at two years 62.6% (vs. 50.2%) [4]. Adjuvant nivolumab had a clear advantage over ipilimumab in terms of side effects. Grade 3 or 4 therapy-associated adverse events occurred in 14.4% of patients in the nivolumab group and 45.9% in the ipilimumab group [3]. Due to side effects, 9.7% and 42.6% of patients discontinued therapy prematurely, respectively. On median, patients received 24 doses of nivolumab (total possible 26) but only four doses of ipilimumab (total possible seven) [3]. Nivolumab as monotherapy is a newly approved adjuvant melanoma treatment option (maximum treatment duration 12 months) for patients with lymph node involvement or distant metastases after complete resection, regardless of BRAF mutation status, the speaker summarized.
4- and 5-year long-term survival with pembrolizumab.
PD Dr. med. Martin Kaatz, Gera, reported on new data on long-term survival of patients with advanced melanoma treated with the antibody pembrolizumab (Keytruda®) directed against the immunoregulatory receptor PD-1. In the KEYNOTE-006 study [5], patients with non-resectable or metastatic melanoma received either pembrolizumab (one infusion every two or three weeks for two years) or ipilimumab (four doses). In case of progression, a second treatment period with pembrolizumab was possible. The rate of 4-year overall survival was 42% in the pooled pembrolizumab arms and 34% in the ipilimumab arm. After progression, repeat pembrolizumab therapy regained response with acceptable tolerability in most patients. So after a relapse, a second pembrolizumab treatment may well be useful, the speaker said. In the KEYNOTE-001 trial, 655 patients with advanced melanoma were treated with pembrolizumab at three different doses. The rate of 5-year overall survival was 34% [6]. This is the longest follow-up for pembrolizumab therapy in melanoma. The data confirm durable and robust antitumor efficacy with manageable safety profiles, the speaker said.
Source: Bristol-Myers Squibb and MSD satellite symposium, 28th German Skin Cancer Congress, September 13-15, 2018, Stuttgart (D).
Literature:
- Wolchok JD, et al: Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377: 1345-1356.
- Schadendorf D, et al: Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase II and III trials. J Clin Oncol 2017; 35: 3807-3814.
- Weber J, et al: Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017; 377: 1824-1835.
- Weber J, et al: Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). ASCO Annual Meeting 2018; Abstract 9502.
- Long GV et al: 4-year survival and outcomes after cessation of pembrolizumab after 2 years in patients with ipilimumab-naive advanced melanoma in KEYNOTE-006. ASCO Annual Meeting 2018; Abstract 9503.
- Hamid O, et al: 5-year survival outcomes in patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. ASCO Annual Meeting 2018; Abstract 9516.
DERMATOLOGIE PRAXIS 2019; 29(1): 26-27
