In patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR mutations, the role of immune checkpoint inhibitors following disease progression with tyrosine kinase inhibitors has been unclear. Several studies reported at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer suggest this approach may be of limited benefit in this subset of patients.

IMpower151, in which 52% of patients had EGFR-mutant lung cancer, did not meet its primary endpoint of investigator-assessed progression-free survival in the intent-to-treat population, reported Caicun Zhou, MD, of Shaghai Pulmonary Hospital, Tongii University School of Medicine, China (Abstract OA09.06). However, the addition of atezolizumab to bevacizumab plus carboplatin/pemetrexed or paclitaxel did numerically improve progression-free survival. “These results are inconsistent with the positive and clinically meaningful progression-free survival and overall survival improvements seen with atezolizumab plus bevacizumab plus carboplatin/paclitaxel in IMpower150,” Dr. Zhou noted.

Reporting the results of the phase II ILLUMINATE trial (Abstract OA09.04), in which all enrolled patients had EGFR mutations, Chee Khoon Lee, MD, of the NHMRC Clinical Trials Centre at the University of Sydney in Australia, said, “The addition of durvalumab and tremelimumab to platinum doublet chemotherapy [showed] modest activity in advanced EGFR-mutant NSCLC following progression on EGFR tyrosine kinase inhibitors.” A subset of patients with T790M wild-type tumors did, however, obtain numerically greater benefit in terms of response and progression-free survival than those with T790M mutations, he added.

About ILLUMINATE

The investigators of the noncomparative phase II ILLUMINATE trial hypothesized that the combination of dual immune checkpoint blockade plus platinum doublet chemotherapy would be superior to platinum doublet chemotherapy alone in patients with EGFR-mutant NSCLC who had experienced disease progression on EGFR tyrosine kinase inhibitors. The study enrolled 100 adult patients in Australia and Taiwan who had exhausted all EGFR tyrosine kinase inhibitor treatments before entry. There were two cohorts of patients:

• Cohort 1 (n = 50): EGFR exon 20 T790M–negative on tissue and plasma biopsy; disease progression on first-line osimertinib or following a single line of first- or second-generation tyrosine kinase inhibitors (upfront osimertinib was later allowed)
• Cohort 2 (n = 50): T790M-positive on tissue and/or plasma biopsy; disease progression on a third-generation EGFR tyrosine kinase inhibitor (ie, osimertinib).

Participants received four cycles of durvalumab at 1,500 mg and tremelimumab at 75 mg in combination with platinum/pemetrexed chemotherapy every 3 weeks, followed by durvalumab at 1,500 mg and pemetrexed at 500 mg/m² maintenance every 4 weeks until disease progression or intolerance to treatment. The primary endpoint was objective response rate. 

After a median follow-up of 22 months, the unconfirmed objective response rate was 42% in cohort 1 and 35% in cohort 2; confirmed response rates were 31% and 21%, disease control rates were 88% and 75%, and median progression-free survival was 6.5 months and 4.9 months, respectively. In T790M-negative patients, high PD-L1 expression (PD-L1 ≥ 50%) was associated with greater benefit vs lower expression.

About IMpower151

The randomized phase II Impower151 trial was initiated in China in 2020 to evaluate 305 patients treated with bevacizumab plus carboplatin and either pemetrexed or paclitaxel, with or without atezolizumab, regardless of EGFR mutation status. In both arms, at least 96% of patients received pemetrexed rather than paclitaxel. Approximately half the patients were never-smokers, 30% had PD-L1 expression ≥ 50%, and approximately 52% had an EGFR mutation.

The primary endpoint—investigator-assessed progression-free survival in the intent-to-treat population—was not met. At a median follow-up of 14 months, the median progression-free survival was 9.5 months for patients receiving bevacizumab plus carboplatin and either pemetrexed or paclitaxel with atezolizumab and 7.1 months with the same regimen sans atezolizumab (hazard ratio [HR] = 0.84, P = .18). At 12 months, 36.9% and 27.7% of patients, respectively, were progression-free.

“We did find [nonsignificant] improvements in progression-free survival in patients with inactive EGFR and ALK,” Dr. Zhou noted. While in mutation-positive patients, the median progression-free survival was 8.5 months in the atezolizumab arm and 8.3 months in the placebo arm (HR = 0.86, 95% confidence interval [CI] = 0.61–1.21), in the wild-type population, these medians were 10.4 months vs 7.0 months (HR = 0.81, 95% CI = 0.55–1.19). In EGFR-mutated patients, 33.4% vs 24.5%, respectively, were progression-free at 1 year; in wild-type patients, these rates were 40.7% and 31.2%, Dr. Zhou reported. 

Conclusions and Next Steps

Referring to the results of both ILLUMINATE and IMpower151, Dr. Lee commented, “I think that with the combined data of what we heard today, it will be difficult to continue advocating for the use of PD-1 and PD-L1 inhibitors in patients with EGFR-mutant lung cancer. I believe that platinum plus pemetrexed should be the standard of care, and that more research is required to find the right biomarker for this patient population.” 

Disclosure: Dr. Zhou reported no conflicts of interest. Dr. Lee has served on advisory boards for Amgen, AstraZeneca, Merck, Merk KGA, Roche, GSK, Novartis, Takeda, Pfizer, and Janssen.