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December 30, 2014 at 11:08 am #22287rick1981Participant
Immunotherapy Combinations in Advanced Melanoma
For patients with metastatic melanoma who do not have an actionable mutation, there are limited treatment options. An option to consider is the administration of ipilimumab as a single agent, or administering chemotherapy until a response is achieved, and then switching to ipilimumab or interleukin-2. “The combination of nivolumab and ipilimumab could be utilized for patients with metastatic melanoma who do not have actionable mutations,” Hamid said.
In a phase I study examining the combination of ipilimumab and nivolumab, the 1- and 2-year overall survival (OS) rate was 85% and 79%, regardless of BRAF and PD-L1 status. However, the objective response rate was 40%, suggesting that a majority of patients do not respond. Patients with BRAF mutations who do not respond can receive a combination of a BRAF and a MEK inhibitor. “Unfortunately, those with BRAF wild-type tumors have even fewer options,” said Sznol.
Combination therapies have generated interest in inhibitor clinical trials, including the exploration of MEK and CDK4/6 inhibition in patients with NRAS-driven melanoma, and combinations of targeted therapies and checkpoint inhibitors. However, in initial studies, the combination of the BRAF inhibitor vemurafenib with ipilimumab was associated with high levels of toxicity, Weber said.
The various BRAF inhibitors demonstrate toxicity differences, especially when used in combination with ipilimumab. To explore these combinations further, a phase I study examined ipilimumab plus dabrafenib with or without trametinib. Dabrafenib plus ipilimumab was well tolerated, without the occurrence of new adverse events. However, the combination of dabrafenib, trametinib, and ipilimumab was associated with a higher rate of grade 3 colitis and perforation.3
Combination studies have shifted toward targeted therapies plus PD-1 and PD-L1 inhibitors. A phase I/ II study is currently looking at the combination of MEDI4736, an anti-PD-L1 antibody, in combination with dabrafenib and trametinib or trametinib alone in patients with advanced melanoma.4 Additionally, a phase IB study is exploring the anti-PD-L1 agent MPDL3280A in combination with vemurafenib.5 The emergence of BRAF mutations in melanomas has resulted in targeted therapies with high response rates, statistically significant progression-free survival (PFS), and OS benefits. These benefits are seen when the MAPK pathway is inhibited at either the BRAF level or downstream MEK.
Pembrolizumab and Nivolumab
On September 4, 2014, the FDA approved pembrolizumab (Keytruda) as a treatment for patients with advanced or unresectable melanoma following progression on prior therapies. This decision makes pembrolizumab the first PD-1 inhibitor to gain approval in the United States.
The accelerated approval was based on response rates demon¬strated in clinical trial data from 173 patients with melanoma in the KEYNOTE-001 study. At the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate (ORR) was 24%, with a response duration lasting from 1.4 to 8.5 months.
The approval was based on a portion of patients enrolled in the phase IB KEYNOTE-001 study that examined pembrolizumab in 276 patients with ipilimumab-naïve (n = 102) and refractory (n = 173) melanoma. In the study, patients received treatment with pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks. The primary endpoint was ORR, with second¬ary outcome measures focused on investigator-assessed immune-related response criteria.
The news about nivolumab is just as promising. A phase III trial of previously treated patients with advanced metastatic melanoma demonstrated that nivolumab (approved in Japan under the brand name Opdivo) demonstrated superior ORR and longer durations of response compared with chemotherapy. 6 These patients were previously treated with anti- CTLA-4 therapy (ipilimumab plus a BRAF inhibitor). In phase I trials of pretreated patients with metastatic melanoma, nivolumab induced tumor regression and showed promise in extending OS, with OS rates of 63%, 48%, and 41% at 1, 2, and 3 years, respectively.
In the data presented at the 2014 ESMO Congress,6 a total of 405 patients with advanced melanoma whose disease progressed after treatment with ipilimumab were evaluated. Patients who tested positive for the BRAF V600 mutation were also included. – See more at:
Treatment continued until progression of disease or unacceptable toxicity. The primary endpoints were ORR and OS. Results were stratified by PD-L1 expression, BRAF status, and best overall response to anti-CTLA-4 therapy. PD-L1 positivity was defined as ≥5% tumor cell membrane staining measured using a proprietary immunohistochemistry assay.
The median time to response favored nivolumab at 2.1 months compared with 3.5 months in the chemotherapy arm. Treatment responses were also longer-lasting in the nivolumab arm. The median duration of response was 3.6 months in the chemotherapy and had not been reached in the nivolumab arm. Responses with nivolumab were observed regardless of pretreatment PD-L1 expression status, BRAF mutation status, and prior anti-CTLA-4 benefit.
In patients with BRAF-mutated melanoma, the ORR was 23% with nivolumab compared with 9% for chemotherapy. In BRAF wild-type patients, the ORR was 34% with nivolumab versus 11% with chemotherapy. Patients with PD-L1 positive tumors (n = 77) experienced an ORR of 44% versus 20% for PD-L1-negative. Side effect profile and toxicity favored nivolumab. The rates of drug-related grade 3/4 adverse events were 9% in the nivolumab arm compared with 31% in the chemotherapy arm. The rates of treatment-related adverse events that led to discontinuation also favored nivolumab over chemotherapy (2% vs 8%). Serious drug-related adverse events of any grade occurred in 6% of nivolumab-treated patients compared with 10% with chemotherapy. Therapies that target the MAPK pathway are a significant advancement in treating metastatic melanoma and may lead to improved patient outcomes and survival. – See more at:
http://www.onclive.com/publications/oncology-live/2014/december-2014/the-evolving-treatment-landscape-in-advanced-melanoma/3#sthash.Ffk7st2U.dpufJanuary 1, 2015 at 7:35 pm #65987goldfidlerParticipant Thank you for this post. Very informative information.
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