Sunday, 31 May 2015

CheckMate 067- Ipi/Nivo versus Ipi versus Nivo



Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067).

Find the original abstract- http://abstracts.asco.org/156/AbstView_156_144621.html

presented by Wolchok

Background: The results of a phase I study in MEL suggested complementary clinical activity with NIVO (a PD-1 checkpoint inhibitor) plus IPI (a CTLA-4 checkpoint inhibitor). Here, we report the results of a randomized, double-blind, phase III trial designed to evaluate NIVO combined with IPI or NIVO alone vs IPI alone in MEL. Methods: Treatment-na├»ve pts (N = 945) were randomized 1:1:1 to NIVO 1 mg/kg Q2W + IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAF mutation status, and M-stage. Co-primary endpoints are progression-free survival (PFS) (reported here) and overall survival (pts continue to be followed). Secondary endpoints include objective response rate (ORR) by RECIST v1.1 and safety. Results: At a minimum follow-up of 9 months, NIVO + IPI and NIVO alone significantly improved PFS and ORR vs IPI (Table). Grade 3-4 drug-related adverse events (AEs) occurred in 55.0%, 16.3%, and 27.3% of pts in the NIVO + IPI, NIVO, and IPI arms, respectively (most commonly diarrhea [9.3%, 2.2%, 6.1%], increased lipase [8.6%, 3.5%, 3.9%], increased alanine aminotransferase [8.3%, 1.3%, 1.6%], and colitis [7.7%, 0.6%, 8.7%]). Drug-related AEs led to discontinuation in 36.4%, 7.7%, and 14.8% of pts in the NIVO + IPI, NIVO, and IPI arms, with 0, 1, and 1 drug-related deaths, respectively. Efficacy outcomes by PD-L1 status will also be presented. Conclusions: NIVO + IPI and NIVO alone had superior clinical activity vs IPI alone. The results with NIVO + IPI and NIVO alone further suggest complementary activity of the two agents. There were no new safety signals or drug-related deaths observed with the combination. Clinical trial information: NCT01844505
NIVO + IPI (N = 314)NIVO (N = 316)IPI (N = 315)
Median PFS,
months (95% CI)
11.5 (8.9–16.7)6.9 (4.3–9.5)2.9 (2.8–3.4)
HR (95% CI)
vs IPI
0.42 (0.31–0.57)*0.57 (0.43–0.76)*--
HR (95% CI)
vs NIVO
0.74 (0.60–0.92)**----
ORR (95% CI)57.6% (52.0–63.2)*43.7% (38.1–49.3)*19.0% (14.9–23.8)
CR rate11.5%8.9%2.2%

*< 0.00001 vs IPI. **Study not statistically powered for this comparison.



NOTES

PFS by PDL1 expression (5% PDL1 expression)

interesting : patients with PDL1 > 5% respond equally well to combo as well as to Nivo alone. HOWEVER, with PDL1 < 5%, patients responded much better to the combo than Nivo alone.

please not that PDL1 expression means different things in different studies- some are > 1%, this is >5% 


and again- response after stopping treatment

67.5% of patients (81/120) who discontinued the combo due to AEs had a response- and half of these occurred AFTER the treatment had ended.

No treatment-related deaths with the combo in this study  (and 1 each for Nivo and Ipi) which shows that safety management is getting better!

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