In advanced non–small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR), 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 Lung Cancer Conference suggest this approach is of limited benefit in this subset.

IMpower151, where 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, though the addition of atezolizumab to bevacizumab plus carboplatin or pemetrexed or paclitaxel did numerically improve progression-free survival, reported Caicun Zhou, MD, of Shanghai Pulmonary Hospital, Tongji University School of Medicine, China.¹ “These results are inconsistent with the positive and clinically meaningful progression-free survival and overall survival improvements seen with atezolizumab plus bevacizumab and carboplatin or paclitaxel in IMpower150,² Dr. Zhou noted.

Caicun Zhou, MD

Chee Khoon Lee, MD

Reporting the results of the phase II ILLUMINATE trial,² where all the patients had EGFR mutations, Chee Khoon Lee, MD, of the NHMRC Clinical Trials Centre at the University of Sydney, Australia, said: “The addition of durvalumab and tremelimumab to platinum-doublet chemotherapy has modest activity in advanced EGFR-mutant non–small cell lung cancer following disease progression on EGFR tyrosine kinase inhibitors.” The subset of patients with EGFR T790M wild-type tumors did, however, obtain numerically greater benefit in terms of response and progression-free survival than those with EGFR T790M mutations, he added.

Referring to the results of both ILLUMINATE and IMpower151, Dr. Lee commented during the discussion: “With the combined data of these two studies, as well as other randomized trials (CheckMate 722 and KEYNOTE-789), it will be difficult to continue advocating for the use of PD-1 and PD-L1 inhibitors in patients with EGFR-mutant lung cancer. Although there is a small subset of patients that will derive benefit from checkpoint inhibitors, we do not yet have a biomarker that can reliably identify these patients. Therefore, I believe that platinum plus pemetrexed should remain the standard of care and that more research is required to better identify who will benefit from checkpoint inhibitors in advanced EGFR-mutant lung cancer.”

About ILLUMINATE

ILLUMINATE is a noncomparative phase II trial led by the Thoracic Oncology Group Australasia, the Taiwan Cooperative Oncology Group, and the NHMRC Clinical Trials Centre of the University of Sydney. The study evaluated outcomes with dual checkpoint inhibition using the anti–PD-L1 agent durvalumab combined with the anti–CTLA-4 antibody tremelimumab. This combination was given with platinum-pemetrexed chemotherapy in 100 patients with metastatic EGFR-mutant lung cancer following disease progression with EGFR tyrosine kinase inhibitors.

Dr. Lee explained: “EGFR tyrosine kinase inhibitors are standard-of-care treatment for advanced untreated EGFR-mutant non–small cell lung cancer, but the majority will develop resistance and disease progression. Anti–PD-L1 and anti–CTLA-4 antibodies have complementary mechanisms of action; when combined with chemotherapy, they may induce more potent immune responses in the ‘immune cold’ EGFR-mutant lung tumor.”

The investigators hypothesized that the combination of dual immune blockade plus platinum doublet chemotherapy would be superior to platinum-doublet chemotherapy in patients with EGFR-mutant disease that progressed on EGFR tyrosine kinase inhibitors. They enrolled adults from 10 Australian and 6 Taiwanese sites 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; disease progression on first-line osimertinib or after a single line of a first- or second-generation tyrosine kinase inhibitor (upfront osimertinib was later allowed)
• Cohort 2 (n = 50): EGFR exon 20 T790M–positive on tissue and/or plasma; 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.

The majority of the patients were female (64%), median patient age was 60, with a good performance status. Most patients were Asian (77%) and never-smokers (73%). EGFR exon 19 deletion was detected in 57% and exon 21 L858R, in 42% of tumors. PD-L1 status (when known) was < 50% in 47 patients and ≥ 50% in 12%.

‘Modest Activity’

After a median follow-up of 22 months, the unconfirmed objective response rate was 42% for cohort 1 and 35% for cohort 2; the confirmed response rates were 31% and 21%, and the disease control rates were 88% and 75%, respectively, Dr. Lee reported.

Median progression-free survival was 6.5 months for cohort 1 and 4.9 months for cohort 2. In cohort 1, patients with PD-L1 expression of ≥ 50% had a median progression-free survival of 13.1 months, whereas those with a PD-L1 < 50% had a median progression-free survival of 4.8 months (P = .0044). No significant difference by PD-L1 expression was seen in patients with EGFR T790M–mutant disease in Cohort 2. No progression-free survival differences were observed according to the type of EGFR mutation. There were also no significant differences in grade 3 or 4 immune-related adverse events between the two cohorts, and the safety profile was consistent with known toxicities of chemoimmunotherapy in advanced lung cancer.

About IMpower151

IMpower151 was designed on the heels of the phase III IMpower150 trial, which found a progression-free and overall survival benefit with atezolizumab vs placebo combined with bevacizumab plus carboplatin or paclitaxel in patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations.³ In that study, a progression-free survival benefit was also observed in the 11% of patients who had sensitizing EGFR or ALK alterations and had experienced disease progression on prior tyrosine kinase inhibitors. The results led to approval of this combination in the United States, European Union, and other regions as first-line treatment for patients with or without EGFR or ALK alterations.

The randomized phase II IMpower151 was initiated in China in 2020 to address regional differences in patient genomic composition and clinical practice. The study’s 305 patients were treated with bevacizumab plus carboplatin and either pemetrexed or paclitaxel (BCP), with or without atezolizumab (BCP vs ABCP), 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 a PD-L1 expression of at least 50%, and approximately 52% had an EGFR mutation. These mutations were exon 19 deletions in approximately 60%, and L858R mutations in approximately 35%. Most patients with EGFR mutations had received prior EGFR tyrosine kinase inhibitors.

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 with ABCP and 7.1 months with BCP (hazard ratio [HR] = 0.84; P = .18). At 12 months, 36.9% and 27.7% of the arms, respectively, were free of disease progression.

“We did find [nonsignificant] improvements in progression-free survival in patients with inactive EGFR and ALK,” Dr. Zhou noted. Although in patients with mutation-positive disease 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 wildtype population, the median progression-free survival was 10.4 months vs 7.0 months (HR = 0.81; 95% CI = 0.55–1.19). In patients with EGFR-mutated disease, 33.4% vs 24.5% of patients, respectively, were progression-free at 1 year; in wild-type patients, these rates were 40.7% and 31.2%, he stated.

Subgroups appearing to derive some benefit from the addition of atezolizumab included males, ever-smokers, patients with liver metastases, patients with L858R mutations, and patients previously treated with only one tyrosine kinase inhibitor.

Overall survival was not mature, with a median of approximately 20 months in each arm. Objective responses were seen in 48% of the atezolizumab arm and 50% of the placebo arm. 

DISCLOSURE: Dr. Zhou reported no conflicts of interest. Dr. Lee has received honoraria from Amgen, AstraZeneca, GSK, Janssen Oncology, Merck KGaA, MSD Oncology, Novartis, Pfizer, Roche, and Takeda; has served as a consultant or advisor to Amgen, AstraZeneca, Merck, Merck KGaA, Novartis, Pfizer, and Takeda; and has received research funding from Amgen, AstraZeneca, Merck KGaA, and Roche.

REFERENCES

1. Zhou C, Dong X, Chen G, et al: IMpower151. 2023 World Conference on Lung Cancer. Abstract OA09.06. Presented September 11, 2023.

2. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018.

3. Lee C, Liao BC, Subramaniam S, et al: ILLUMINATE. 2023 World Conference on Lung Cancer. Abstract OA09.04. Presented September 11, 2023.