Right Patient for Immunotherapy in NSCLC Explored

Matthew D. Hellmann, MD

Multiple trials are ongoing in non-small cell lung cancer (NSCLC) with immunotherapy agents such as ipilimumab, nivolumab, and pembrolizumab.^1-3As with most cancers, however, there is also a need to identify (for example, with the use of biomarkers) which types of patients with NSCLC might benefit the most from these new therapies.^4,5

With lung cancer in particular, there is a need to optimize therapy for selected patient groups such as the elderly, and those with comorbid conditions.⁶Indeed, some chemotherapy trials in NSCLC have focused primarily on elderly patient populations.⁷Because immunotherapies may offer a less toxic alternative to conventional chemotherapies, it will be important for trials to be conducted in such populations.

Commenting on the status of patient selection for immunotherapy in NSCLC, Matthew D. Hellmann, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, noted, “Although the question is a good and important one, I don’t think there is a good answer yet in terms of which patients with lung cancers are most likely to benefit from immunotherapies.”

There remains a significant unmet need to improve survival in patients with NSCLC despite ongoing improvements in therapy and development of advanced chemotherapies.⁴The use of immunotherapies in NSCLC remains, at least in theory, an especially attractive option because of their antitumor specificity and potential for long-term disease control via the induction of T-cell memory.⁴Indeed, some 5% to 8% of patients with melanoma have derived long-term benefits from immunotherapy, with stable and/or responsive disease for years after the use of anti- cytotoxic T-lymphocyte antigen-4 (CTLA-4) agents.^2,8,9

Also, there is some evidence that certain patients could have a so-called ‘favorable’ immune phenotype and may benefit more from immunotherapies, and such patients can be identified through genetic testing.¹⁰

Other evidence in NSCLC suggests that modulation of the antitumor immune response could be beneficial in terms of outcomes. For example, studies have shown that T-regulatory cells inhibit cytotoxic responses in lung carcinoma, and, in patients with squamous cell NSCLC, active tuberculosis infection has a beneficial effect on survival, suggesting that active T-cell immunity enhances the local antitumor response.^11,12

There is also interest in combining checkpoint inhibitors with established chemotherapy in lung cancer, on the hypothesis that induction of tumor-specific immunity can be enhanced by the release of tumor antigens resulting from chemotherapy-induced cytolysis.^4,13Toward this end, results of a phase II study (CA 184—041) showed that phased use of ipilimumab in combination with a paclitaxel-carboplatin regimen significantly improved progression-free survival over the chemotherapy combination alone.¹⁴

Transient depletion and regeneration of T cells after chemotherapy may also serve to enhance antitumor immunity in patients with malignant mesothelioma or NSCLC.¹⁵In one study, an increase in CD8+ T-cell proliferation, and in their overall proportion relative to the T-regulatory cell pool, had a positive impact on survival.¹⁵These and other findings suggest a benefit of transient chemotherapy-induced lymphodepletion through regeneration of the T-cell pool and this impact may be further enhanced by adding checkpoint inhibitors in NSCLC.¹⁵

While studies such as CA 184—041 have shown a benefit of the anti-CTLA-4 antibody ipilimumab in advanced disease, there may also be potential for using these types of therapies earlier in disease, such as in the adjuvant or neoadjuvant setting or as maintenance therapy after chemotherapy induction.⁴

Another class of checkpoint inhibitors, anti-programmed death 1 (PD-1) agents, has also shown promise in the treatment of NSCLC. The interaction of the PD-1 receptor on T cells with its ligand, PD-L1, constitutes an important level of immune regulation to prevent autoimmunity and uncontrolled T-cell responses.^2,3Tumors, including those in lung cancer, are believed to exploit this pathway to evade immune surveillance by expressing the PD-L1 ligand on the cell surface.^2,3In this regard, sarcomatoid lung tumors, a rare subtype that is highly aggressive and resistant to chemotherapy, have been shown in a recent study to have a relatively high expression of PD-L1 (69.2%), which was determined to be ~40% higher than in other types of NSCLC (27.4%).¹⁶These findings would suggest that therapies directed against PD-1 or PD-L1 agents could be especially beneficial to this aggressive subtype of NSCLC.¹⁶

Accordingly, the PD-L1 ligand is a rational choice of biomarker to identify patients likely to benefit from anti-PD-1 agents (eg; nivolumab, pembrolizumab); however, according to Hellmann, the situation is more complicated than simply identifying patients with tumors expressing PD-L1.

Clinical Pearls

• Checkpoint inhibitors are an effective and potentially less toxic therapy for patients with non-small cell lung cancer (NSCLC).
• There is no clinical evidence to identify any specific subgroup of patients with NSCLC who will benefit from immunotherapy with checkpoint inhibitors.
• Although there are rational biomarkers such as PD-L1 that can be assessed, PD-L1 expression does not appear to predict either response or lack of response.
• Response to immunotherapy with checkpoint inhibitors does not appear to be better or worse in younger versus older patients, or in those with comorbid conditions.

“Expression of PD-L1 is being tested as a potential biomarker of response to anti-PD-1/PD-L1 therapies in several studies. PD-L1 expression does appear to enrich for response, but the presence of PD-L1 expression doesn’t guarantee response, and the lack of PD-L1 expression doesn’t prohibit the potential for response. We know that approximately 15%-20% of patients with lung cancers can benefit from anti-PD-1 therapies. Identifying reliable predictors of response to immunotherapies is one of the critically important challenges as we move forward,” Hellmann said.

Hellmann also added that, at least at present, there appear to be no particular differences in the response to immunotherapy between younger and older patients or in the context of specific comorbid conditions.

References

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