Immunotherapy Changing NSCLC Care, But Many Questions Remain

Immunotherapy has ushered in a new era in the treatment of non–small cell lung cancer (NSCLC), but a new review article notes significant questions remain in terms of understanding which patients benefit most from the therapy and how best to administer it.

Investigators discussed the latest findings in Seminars in Oncology. “Therapeutic decisions in advanced (metastatic) NSCLC have become more complex as the number of available treatment options has increased,” they noted.

Factors such as the presence of driver mutations and programmed death-ligand 1 (PD-L1) expression level are key data points in making treatment decisions, they said. In addition, patient performance status and comorbidities must be considered.

In patients with PD-L1 expression levels at or above 50%, single-agent checkpoint inhibitors such as pembrolizumab (Keytruda), cemiplimab (Libtayo), and atezolizumab (Tecentriq), have been shown to work well vs chemotherapy, the authors said. However, in patients with PD-L1 levels of 1% to 49%, evidence suggests overall survival (OS) rates from single-agent PD-L1 inhibition are lower. Thus, chemo-immunotherapy combinations are preferred for such patients, so long as they can tolerate the therapy.

The authors said dual PD-L1 inhibition and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibition is also available and is drawing significant attention as a chemotherapy-free treatment option. Yet, they said no head-to-head trial findings are available showing how dual inhibition performs against pembrolizumab alone or with chemotherapy. In the absence of such a trial, existing data suggest dual inhibition is not superior. Thus, they said, they tend to prefer pembrolizumab-based combinations without a CTLA-4 inhibitor, “unless there are compelling reasons or strong patient preference to avoid cytotoxic chemotherapy.”

In nonmetastatic cases, surgery and radiation or concurrent chemo-radiation are the “mainstay of curative-intent treatment of NSCLC,” the authors said. But there have been clinical trials evaluating the use of immune checkpoint inhibitors (ICIs) in these patients.

“Overall, the results of these nonmetastatic ICI trials are encouraging and expand the population of patients who may derive benefit from ICI therapy,” they wrote. “However, much remains to be elucidated.”

Those questions include whether EGFR mutational status matters in the regimen’s efficacy, they said. Looking forward, the authors said the current body of scientific evidence suffers from a lack of representation of key demographic groups. Although patients who are Black have a lower incidence of lung cancer compared with non-Hispanic Whites, they face a lower 5-year survival rate. One reason, the authors said, could be their inequitable representation in clinical trials.

They said the VA system offers a unique opportunity to incorporate underrepresented groups into future studies.

“VA health care system patients were found to be more likely to be African American and had a lower annual income when compared to the general US population,” they said. “On average, veterans have been found to have a higher comorbidity burden.”

Moreover, lung cancer is prevalent in the VA health system, many patients in the system are being treated with immunotherapy, and their data can provide for meaningful study, including real-world data.

The investigators noted that a previous retrospective analysis of real-world VA data showed veterans receiving ICI therapy for multiple tumor types had worse survival outcomes than those of the pivotal clinical trials, but those outcomes still exceeded standard-of-care therapies.

“These signals make it imperative to continue to generate a higher level of evidence with the gold standard of prospective randomized controlled trials with the inclusion of the veteran population,” they concluded.

Reference

Huang Q, Kemnade J, Cornwell L, Kheradmand F, Sabichi A, Das D. Non-small cell lung cancer in the era of immunotherapy. Semin Oncol. Published online July 8, 2022. doi:10.1053/j.seminoncol.2022.06.009