TP53– KRAS co-mutations predicted longer PFS on immunotherapy whereas either TP53 or KRAS mutations alone did not (Figure 2). Conversely, KRAS mutations were associated with better ORR and PFS in TP53-mutant but not in TP53-wildtype patients. TP53 mutations were shown to be associated with higher ORR and PFS in patients with KRAS mutations, but not in the KRAS wildtype population. investigated the interrelation between these two gene mutations with respect to the prediction of immune checkpoint inhibition efficacy in EGFR/ ALK wildtype, non-squamous NSCLC. Using a meta-cohort analysis of 8 cohorts including a total of 1,129 patients, Li et al. Genetic aberrations in the KRAS and TP53 genes are common in NSCLC. KRAS & TP53 mutations: predicting IO efficacy As the authors summarized, pembrolizumab monotherapy remains a standard-of-care first-line treatment for NSCLC patients with TPS ≥ 50 % who do not harbor EGFR/ ALK aberrations. Moreover, the combination of pembrolizumab and ipilimumab gave rise to greater toxicity than pembrolizumab alone. KEYNOTE-598 was stopped for futility based on the recommendation of the data monitoring committee. No differences were observed regarding OS (21.4 vs. However, adding ipilimumab to pembrolizumab did not improve efficacy compared with pembrolizumab alone.
#Keynote 189 plus
The KEYNOTE-598 study included 284 patients in each arm those in the experimental arm received pembrolizumab for up to 35 doses plus ipilimumab for up to 18 doses, while those in the control arm were treated with pembrolizumab plus placebo. Appropriately powered, controlled comparisons of anti–PD-1 monotherapy versus dual PD-1 and CTLA-4 inhibition as first-line treatment for NSCLC had been lacking to date. KEYNOTE-598 tested this approach based on the fact that dual immunotherapy with the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab is a standard of care for advanced melanoma and renal cell carcinoma. Negative results were obtained in the KEYNOTE-598 study for pembrolizumab plus ipilimumab as first-line therapy of patients with stage IV NSCLC and PD-L1 TPS ≥ 50 % who had no targetable EGFR/ ALK alterations.
Pembrolizumab plus ipilimumab: KEYNOTE-598 Forty-five patients (80.4 %) were alive at data cut-off 28 of them showed no signs of disease progression. Objective responses occurred in 87.5 %, with complete responses resulting in 10.7 %. In the group of patients who completed 35 cycles of pembrolizumab, the 2-year OS rate from completion of this treatment was 79.6 %. 19.9 %, and responses lasted for a median of 12.6 vs.
PFS2, which was defined as the time from randomization to investigator-assessed disease progression that led to cessation of second-line therapy, start of third-line therapy, or death, was 17.0 vs. OS and PFS benefits emerged irrespective of PD-L1 baseline expression. 10.6 months in the ITT population, with the 3-year OS rate being almost doubled in the experimental arm (31.3 % vs. Pembrolizumab plus platinum/pemetrexed continued to provide OS and PFS benefits compared to placebo plus chemotherapy, while showing a manageable safety profile. presented updated efficacy and safety outcomes for the overall study population (intent-to-treat, ITT) as well as for patients who completed 35 cycles, i.e., 2 years of pembrolizumab (n = 56).
After a median follow-up of 46.3 months, Gray et al. Risk reductions of approximately 50 % were achieved with the immunotherapy-based strategy for both OS and PFS (HRs, 0.49 and 0.52, respectively). Pembrolizumab plus platinum/pemetrexed for up to 4 cycles followed by pembrolizumab for up to 31 cycles plus pemetrexed (n = 410) was tested against placebo plus platinum/pemetrexed followed by placebo plus pemetrexed (n = 206).
#Keynote 189 trial
Substantial OS and PFS improvements have led to the implementation of the regimen evaluated in the KEYNOTE-189 trial as standard first-line approach for stage IV non-squamous NSCLC without sensitizing EGFR/ ALK alterations.
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