Immunotherapy not effective for EGFR-mutant lung cancer

EGFR mutational status can predict which patients with metastatic non-small cell lung carcinoma (NSCLC) derive benefit from checkpoint inhibitor therapy, according to research published in JAMA Oncology.

In a new systematic review and meta-analysis, checkpoint inhibition preferentially prolonged overall survival (OS) when compared with docetaxel in patients with previously treated advanced NSCLC who did not have EGFR-mutant tumors. No benefit was found in patients with EGFR-mutant tumors.

“Our results have several important clinical and research implications,” wrote the researchers, led by Chee Khoon Lee, MBBS(Hons), FRACP, PhD, from the University of Sydney, New South Wales, Australia. “They might be useful for the selection of patients for checkpoint inhibitor therapy and would enhance drug development and the design and interpretation of future clinical trials. For patients with EGFR mutant NSCLC, our findings suggest immunotherapy should be considered only after exhaustion of other effective therapeutic options, such as EGFR tyrosine kinase inhibitors (TKI) and chemotherapy.” 

An EGFR TKI is recommended in the National Comprehensive Cancer Network (NCCN) NSCLC guideline as first-line therapy for the management of patients who have EGFR-sensitizing mutation and continuation of an EGFR TKI after disease progression. In the latest version of the NCCN guideline (v3.2018), immunotherapy was removed as recommended subsequent therapy for patients with EGFR mutations who progress on initial therapy.

Immune checkpoint inhibitors have revolutionized the treatment of metastatic NSCLC. The PD-1/PD-L1 inhibitors have become standard second-line therapy in patients who progress on first-line therapy based on durability of response and long-term improvements in OS, but only a small proportion of patients respond.

The clinicopathologic characteristics of responders to immune checkpoint inhibition had not been adequately defined, although previous studies provided a clue that any benefit is modest in tumors harboring EGFR mutations.

The meta-analysis included five clinical trials that involved 3,025 patients with advanced NSCLC who were randomized to receive a checkpoint inhibitor or docetaxel as second-line therapy. In the groups randomized to checkpoint inhibition, 427 were assigned to nivolumab, 691 to pembrolizumab, and 569 to atezolizumab. The other 1,338 patients were assigned to docetaxel.

Treatment with a checkpoint inhibitor compared with docetaxel chemotherapy resulted in a 31% reduction in the risk of death (HR: 0.69; P  < 0.001) in the intention-to-treat population, with no significant heterogeneity in the overall treatment effect across the five trials (χ²=3.11; P =0.68).

The benefit in OS was realized in patients with EGFR wild-type tumors (HR: 0.67; P < 0.001), but not in patients with EGFR-mutated NSCLC (HR: 1.11; P=0.54).

KRAS status of patients was available for only three of the five clinical trials, and KRAS could not be assessed in 82.8% of the entire patient population. When the results from these three trials were analyzed by KRAS mutation status, immune checkpoint inhibition was found to prolong OS in the KRAS-mutant subgroup (HR: 0.65; P=0.03) but not in the KRAS-wild-type subgroup (HR: 0.86; P=0.24).

However, “in the absence of a statistically significant interaction between KRAS status and treatment effect (KRAS mutant HR: 0.86 vs KRAS wild-type HR: 0.65; P=0.24), this meta-analysis does not provide sufficient evidence to recommend KRAS as a predictive biomarker for the selection of patients for checkpoint inhibitor therapy,” the investigators wrote. 

No other patient or disease factor was found to influence the treatment benefit of checkpoint inhibitors, including smoking status, performance status (0 or 1), age, histology, brain metastases, and sex.

“Despite the high expression of PD-L1 in EGFR mutant tumors, we have previously hypothesized that the low mutational load associated with these tumors, as compared with other types of NSCLC, might provide a biological explanation for our findings,” the authors postulated. “Other recent insights that may help to further elucidate the mechanisms of resistance include the finding that EGFR mutant tumors are associated with a high frequency of inactive tumor-infiltrating lymphocytes even though lymphocytes are present in the tumor microenvironment.”

To read more about this study, click here.