Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study.

Abstract

LBA9000 Background: EGFR TKIs are standard 1L therapy for metastatic NSCLC with sensitizing EGFR mutations; however, most patients (pts) ultimately experience PD. We report the protocol-specified final analysis (FA) from the randomized, double-blind, phase 3 KEYNOTE-789 study of pemetrexed (pem) and platinum-based chemotherapy (chemo) with or without pembrolizumab (pembro) as subsequent therapy for pts with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (NCT03515837). Methods: Adults with histologically or cytologically confirmed stage IV nonsquamous NSCLC, ECOG PS of 0 or 1, documented DEL19 or L858R EGFR mutation, and progression after EGFR TKI treatment were enrolled. Pts were randomized 1:1 to 35 cycles of pembro 200 mg Q3W or placebo (pbo) Q3W plus 4 cycles of pem and carboplatin or cisplatin Q3W followed by maintenance pem. Randomization was stratified by PD-L1 TPS (<50% vs ≥50%), prior osimertinib (yes vs no), and region (East Asia vs not East Asia). Dual primary endpoints were PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. ORR and DOR per RECIST v1.1 by BICR and safety were secondary endpoints. Final PFS testing was completed at the second interim analysis (IA2; data cutoff, Dec 3, 2021); all other endpoints were assessed at FA (data cutoff, Jan 17, 2023). Efficacy boundaries based on actual observed events were 1-sided P = 0.0117 for PFS (IA2) and P = 0.0118 for OS (FA). Results: 492 pts were randomized to pembro + chemo (n = 245) or pbo + chemo (n = 247). At IA2, median PFS (95% CI) was 5.6 (5.5–5.8) mo with pembro + chemo vs 5.5 (5.4–5.6) mo with pbo + chemo; HR 0.80 (95% CI, 0.65–0.97); P = 0.0122; and the results did not reach statistical significance. Median (range) time from randomization to data cutoff at FA (Jan 17, 2023) was 42.0 (29.5–53.9) mo. At FA, median OS (95% CI) was 15.9 (13.7–18.8) vs 14.7 (12.7–17.1) mo. While the HR for OS (0.84 [95% CI, 0.69–1.02]; P = 0.0362) favored pembro + chemo vs pbo + chemo, it did not reach statistical significance. OS rates at 12-mo were 61.6% vs 59.4% and at 24-mo were 30.6% vs 26.4%. HR for OS was similar in PD-L1 TPS ≥50% (HR, 0.84) and TPS <50% groups (HR, 0.85). ORR (95% CI) in ITT was 29.0% (23.4%–35.1%) with pembro + chemo vs 27.1% (21.7%–33.1%) with pbo + chemo. Median DOR was 6.3 (2.3 to 40.8+) mo vs 5.6 (1.8+ to 40.6+) mo. Grade ≥3 treatment-related AEs occurred in 43.7% of pts in pembro + chemo arm and 38.6% in pbo + chemo arm; grade 5 AEs occurred in 0.4% vs 0.8%. Grade ≥3 immune-mediated AEs and infusion reactions occurred in 4.5% of pts in the pembro + chemo arm and 2.0% in the pbo + chemo arm; 0.4% vs 0% had grade 5 events. Conclusions: In the KEYNOTE-789 study, addition of pembro to chemo in pts with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS and OS in comparison to pbo + chemo. AEs were manageable in both arms, and no new safety signals were identified. Clinical trial information: NCT03820986 .

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

“…However, pemetrexed based platinum combination has been widely used not only in clinical practice but also in clinical trials. 10,11,22 Finally, the absence of OS benefit is observed in the current analysis, which needs longer follow-up.…”

“…Similar trends were observed in CheckMate-722 and KEYNOTE-789, where PFS benefit in PD-L1 ≥50% with an HR of 0.64 (95% CI, 0.36 to 1.15) and OS benefit in PD-L1 ≥1% with an HR of 0.77 (95% CI, 0.58-1.02) were noted, respectively. 10,11 Simultaneously, patients with highly inflamed tumors, as measured by the density of TIL, responded favorably to the ABCP regimen, indicating the essential role of bevacizumab in increasing the sensitivity of atezolizumab by reversing the immunosuppressive tumor microenvironment enriched with TILs in EGFR -mutated NSCLC. 26,27 Further biomarker research is required to identify which patients will benefit from these agents.…”

“…In contrast, two global randomized studies (CheckMate-722 and KEYNOTE-789) comparing chemotherapy plus ICI versus chemotherapy alone in EGFR -mutated NSCLC who had progressed on EGFR TKI failed to demonstrate any clinical benefit, suggesting the role of antiangiogenic agent combined with ICI in EGFR -mutated NSCLC. 10,11…”

“…As a consequence, platinum-based chemotherapy is the standard of care for patients with EGFR TKI failure. 11…”

Combining Genomic Biomarkers to Guide Immunotherapy in Non–Small Cell Lung Cancer

“…These signals of activity could shed new light on studies testing ICB treatment in populations carrying these resistance markers. For example, the KEYNOTE-789 study ( 37 ) found a modest benefit of ICB plus chemo versus chemo-alone in patients with TKI resistant, EGFR mutant NSCLC; however, this study just failed to attain the predefined efficacy boundaries of P = 0.0117 for PFS and P = 0.0118 for OS. Our results suggest that it is important to study whether this modest benefit of the ICB plus chemo combination in this setting is more pronounced in the context of a high TMB.…”