Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL).

Abstract

LBA9003^ Background: We report updated survival and clinical activity in initially enrolled cohorts and activity by BRAF MT status in a phase I trial of concurrent and sequenced NIVO + IPI. Methods: MEL pts (n=53, enrolled 2009-2012, data analysis Dec 2013) with ≤3 prior therapies received IV concurrent NIVO + IPI, Q3Wk × 4 doses, followed by NIVO Q3Wk × 4. At wk 24, NIVO + IPI continued Q12Wk × 8 in pts with disease control and no DLT. Tumor responses were evaluated by WHO and immune-related criteria. Results: Pt characteristics included stage M1c: 55% and prior systemic therapy: 40%. Across doses, 1- and 2-y OS rates were 82% and 75%. Clinical activity was similar to previous reports except CRs rose to 9/53 (17%). Pts with/without tumor BRAF MT (n=36) had similar activity (Table). By wk 36, 42% demonstrated ≥80% tumor reduction. Median duration of response (DOR) was not reached (NR). Of 22 pts with objective response, 14 (64%) had DOR ≥24 wk (range: 25+, 106+). Treatment-related adverse events were as reported previously: grade 3-4, 53% of pts; most common: ↑ lipase and AST (13% ea). Data for sequenced cohorts are shown (Table). Conclusions: Concurrent NIVO + IPI therapy showed encouraging survival and a manageable safety profile in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in the majority of pts. Forty additional pts were enrolled (last pt: Nov 2013) on a cohort of NIVO 1 mg/kg + IPI 3 mg/kg Q3Wk × 4 doses, followed by NIVO 3mg/kg Q2Wk (the selected regimen for phase II/III trials). Clinical trial information: NCT01024231. [Table: see text]

New Strategies in Melanoma: Entering the Era of Combinatorial Therapy

“…More remarkably, each responder had at least an 80% reduction in measured tumor volume and 2-year survival rates are approximately 70% (66). Not unexpectedly, this combination was associated with substantial immune-related toxicity, and grade 3/4 adverse events were seen in over 50% of patients (16,66). Whether this combination (or that of ipilimumab plus pembrolizumab; NCT02089685) ultimately proves more effective and is manageable in routine clinical practice compared with sequential single-agent therapy strategies (NCT01783938, NCT01927419, NCT01844505) with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies remains to be seen, though this trial clearly demonstrates the potential of combined targeting of immune checkpoints, and has been quickly followed by a number of similar trials (Table 1).…”

“…In the original publication, the data from the first 53 treated patients were reported, and evidence of clinical activity was seen in 65% of patients with 53% of patients having a protocol-defined response, (16). More remarkably, each responder had at least an 80% reduction in measured tumor volume and 2-year survival rates are approximately 70% (66). Not unexpectedly, this combination was associated with substantial immune-related toxicity, and grade 3/4 adverse events were seen in over 50% of patients (16,66).…”

Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade

“…Survival updates for these patients showed 1-and 2-year overall survival rates of 82% and 75%, respectively. The objective response rate was 40%, and the median duration of response was not reached, indicating ongoing responses for many patients (84).…”

Immune Checkpoint Blockade in Cancer Therapy

“…A phase I study of ipilimumab and nivolumab in patients with melanoma resulted in a high durable response rate and impressive overall survival compared with historical data. 109,110 Although the most recently reported grade 3 or 4 toxicity rate in patients with melanoma was 64%, which is higher than either ipilimumab or nivolumab individually, 111 the vast majority of these irAEs were asymptomatic laboratory abnormalities of unclear clinical consequence. For example, elevations in amylase or lipase were reported in 21% of patients, none of whom met clinical criteria for a diagnosis of pancreatitis.…”