Nivolumab/Ipilimumab Significantly Improves PFS in TMB-High NSCLC

Matthew D. Hellmann, MD

The 1-year progression-free survival (PFS) rate was more than tripled with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) versus chemotherapy in treatment-naïve patients with non—small cell lung cancer (NSCLC) with high tumor mutation burden (TMB), according to initial findings from the phase III CheckMate-227 trial. The trial results were presented at the 2018 AACR Annual Meeting and published online in theNew England Journal of Medicine(NEJM).^1,2

The 1-year PFS rate was 43% for patients with high TMB (&ge;10 mutations/megabase) assigned to the immunotherapy combination compared with 13% for those assigned to platinum-doublet chemotherapy. The median PFS was 7.2 months versus 5.5 months, respectively, representing a 42% reduction in risk of disease progression or death (HR, 0.58; 97.5% CI, 0.41-0.81;P<.001).

The combination was well tolerated and safety was similar to previous results with the therapies. The rate of grade 3/4 treatment-related adverse events (TRAEs) was 31% in the immunotherapy combination arm versus 36% with chemotherapy.

&ldquo;In this study of TMB-high non—small cell lung cancer, we found that nivolumab plus ipilimumab significantly improved progression-free survival compared to chemotherapy,&rdquo; lead author Matthew D. Hellman, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center, said at an AACR press conference.

&ldquo;The breadth, duration, and depth of response were all substantially improved, with a more than tripling of the 1-year PFS with the immunotherapy combination. This benefit was independent of PD-L1 as well as histology,&rdquo; added Hellman.

These data represent part 1 of a 3-part trial in patients with stage IV or recurrent NSCLC who had not received prior treatment. Patients with a PD-L1 expression level &ge;1% were stratified into squamous and nonsquamous groups and assigned to 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks (n = 139), 360 mg of nivolumab plus platinum-doublet chemotherapy depending on histologic subtype (n = 71), or 500 m2 of pemetrexed plus 5 or 6 AUC of carboplatin or 75 m2 of cisplatin every 3 weeks for 4 cycles (n = 160).

The objective response rate was 45.3% with the immunotherapy combination versus 26.9% with chemotherapy. Among responders, 68% had an ongoing response after 1 year with nivolumab/ipilimumab, versus 25% with chemotherapy.

Overall survival (OS) data are not yet mature, but Hellman said the preliminary results are encouraging. The HR for OS at the cutoff for TMB-high patients was 0.79 (95% CI, 56-1.10).

&ldquo;At this point, more than 50% of the data points are censored. Nearly all data points beyond 14 months are censored and still, there&rsquo;s a clear trend in improvement in survival with nivolumab plus ipilimumab,&rdquo; said.

The median PFS did not favor the combination in the overall population (4.9 vs 5.5 months), though the combination was associated with a higher 1-year PFS rate (30.9% vs 17.0%; HR, 0.83; 95% CI, 0.72-0.96). Among patients with a low tumor mutational burden (<10 mutations/megabase), the median PFS was 3.2 months with nivolumab plus ipilimumab versus 5.5 months with chemotherapy (HR, 1.07; 95% CI, 0.84-1.35).

In TMB-high patients assigned to the immunotherapy combination, 24.4% were still on treatment at the January 24, 2018, database lock compared with 3.1% treated with chemotherapy. Of patients initially assigned to chemotherapy, 30% received subsequent immunotherapy.

Subgroup analysis showed that the combination improved PFS among patients with PD-L1 expression &ge;1% and <1%. The combination also improved PFS in both the squamous and nonsquamous subtypes.

&ldquo;This result highlights that TMB and PD-L1 are independent biomarkers, that TMB is predictive of benefit with nivolumab plus ipilimumab irrespective of PD-L1, and that TMB-high represents a distinct subgroup of non—small cell lung cancer,&rdquo; Hellman said.

CheckMate-227 also compared chemotherapy versus nivolumab monotherapy among patients with &ge;13 mutations/megabase and PD-L1 &ge;1%. Median PFS was 4.2 months with nivolumab compared with 5.6 months with chemotherapy (HR, 0.95; 95% CI, 0.61-1.48;P= .78). Among patients with &ge;10 mutations/megabase and PD-L1 &ge;1%, median PFS was 7.1 months with nivolumab plus ipilimumab versus 4.2 months for nivolumab monotherapy (HR, 0.75; 95% CI, 0.53-1.07).

Rash, diarrhea, and anemia (1.6% each) were the most common grade 3/4 TRAEs in the combination arm. Twelve percent of patients in the combination arm discontinued due to TRAEs compared with 4.9% in the chemotherapy arm and 6.9% in the nivolumab monotherapy arm.

References:

1. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT077. 2017;35(suppl 4S; abstr 350).
2. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018].N Engl J Med. doi: 10.1056/NEJMoa1801946.