Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722

Abstract

Purpose: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs).

Methods: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR).

Results: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively.

Conclusion: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

FIG 1.

CONSORT diagram of patient disposition. ^aIncludes 73 patients randomly assigned to the nivolumab plus ipilimumab arm that was closed during enrollment. Database lock on April 25, 2022, with a minimum follow-up of 18.2 months and a median follow-up of 38.1 months. AE, adverse event.

FIG 2.

PFS in all randomly assigned patients. (A) PFS by BICR and (B) PFS subgroup analysis with stratification factors in bold. PFS by BICR in patients with (C) sensitizing EGFR mutations, (D) one line of previous EGFR TKI therapy, and (E) sensitizing EGFR mutations and one line of previous EGFR TKI therapy. ^aStratified HR, 0.75. ^bRace was reported as other for one patient in nivolumab plus chemotherapy arm. ^cTumor PD-L1 expression was not evaluable in 31 patients (17 in nivolumab plus chemotherapy arm, and 14 in chemotherapy arm), and not reported for one patient in nivolumab plus chemotherapy arm. ^dType of EGFR mutation was not reported in one patient in nivolumab plus chemotherapy arm. ^eIncludes exon 19 deletion and L858R mutation. ^fWithout any sensitizing mutations (T790M, L861Q, exon 20 insertion, G719X, S768I, and other). ^gTwo patients in the chemotherapy arm had received three lines of previous EGFR TKI. BICR, blinded independent central review; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

FIG 3.

PFS by BICR in patients with (A) tumor PD-L1 <1%, (B) tumor PD-L1 ≥1%, (C) tumor PD-L1 1%-49%, and (D) tumor PD-L1 ≥50%. BICR, blinded independent central review; HR, hazard ratio; PFS, progression-free survival.

FIG 4.

OS in all randomly assigned patients. HR, hazard ratio; OS, overall survival.

FIG 5.

ORR by BICR and DOR in all randomly assigned patients. BICR, blinded independent central review; DOR, duration of response; ORR, objective response rate.