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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).
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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.
|NIVO (mg/kg) +
IPI (mg/kg) [n]
|1-Y OS rate,
% [pts at risk]
|ACAR by BRAF
MT status,* % [n]
|0.3 + 3 ||56 ||14.8||57||50 ||67 ||57 |
|1 + 3 ||94 ||NR||65||50 ||50 ||78 |
|3 + 1 ||89 ||NR||81||67 ||85 ||– |
|3 + 3 ||100 ||NR||83||100 ||75 ||100 |
|Concurrent ||82 ||39.7||70||60 ||73 ||71 |
|13.0||44||44 ||47 ||38 |
n: no. response-evaluable pts. ACAR: aggregate clinical activity rate = CR+PR+uCR+uPR+irCR+irPR+SD ≥24 wk+ irSD ≥24 wk. *Retrospective analysis. †Pts began NIVO Q2Wk × 48 doses within 4-12 wk after last IPI dose.
Abstracts by Mario Sznol:
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Presentations by Mario Sznol:
Safety and antitumor activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies.Meeting: 2010 ASCO Annual Meeting Abstract No: 2506Session: Developmental Therapeutics - Clinical Pharmacology and Immunotherapy (Oral Abstract Session)