The Role of PD-1/PD-L1 Inhibitors in the Adjuvant Setting for NSCLC

The Role of PD-1/PD-L1 Inhibitors in the Adjuvant Setting for NSCLC

In the following article, Grace K. Dy, MD, answers a question posed by an attendee during a 2015 Best of ASCO® Meeting. Dr. Dy is an associate professor of oncology at Roswell Park Cancer Institute.

Dr. Grace K. Dy

Question: What is the role of PD-1/PD-L1 inhibitors in the adjuvant setting for non–small cell lung cancer (NSCLC)?

Answer: Currently, PD-1/PD-L1 checkpoint inhibitors represent a major class of breakthrough therapy across multiple malignancies. In metastatic NSCLC, nivolumab, a fully human IgG4 anti–PD-1 monoclonal antibody, conferred superior objective response rate (ORR) and overall survival (OS) as second-line therapy compared to docetaxel in separate randomized phase III CHECKMATE trials for squamous and nonsquamous NSCLC histologic subtypes.1,2 Time to objective response was similar between nivolumab and docetaxel, quelling concerns about early disease control with immunotherapeutic agents. Importantly, treatment-related serious adverse events occurred less frequently with nivolumab.

Another clinically relevant difference is that among patients with objective response to therapy, duration of disease control is sustained much longer with nivolumab. This durable response likely contributes to the difference in 1-year progression-free survival rate, which is 2.5 to 3.5 times higher with nivolumab (19% to 21%) compared to docetaxel (6% to 8%). Pembrolizumab, a humanized IgG4 anti–PD-1 monoclonal antibody, similarly showed superior ORR, durable response, and OS compared to docetaxel in the randomized phase II/III KEYNOTE 010 study for metastatic NSCLC.3

Because the PD-1/PD-L1 pathway has a pivotal role in dampening immunosurveillance of tumors, and based on the efficacy and toxicity profile seen with these agents to date, using checkpoint inhibitors earlier in the course of NSCLC management is the subject of a wide variety of studies. It is anticipated that anti–PD-1/PD-L1 inhibitors will soon be incorporated as first-line therapy in the metastatic setting, potentially even supplanting platinum-based regimens for many patients with advanced NSCLC, pending maturation of data from several completed or ongoing clinical trials (NCT02578680, NCT02477826, NCT02542293, NCT02453282, NCT02041533, and NCT02576574).

Moreover, their role as consolidation therapy after definitive chemoradiation for locally advanced NSCLC is also being investigated (NCT02125461). Therefore, it is not surprising that nivolumab and pembrolizumab are being evaluated as adjuvant therapy for patients with resected stage IB (> 4 cm) to IIIA NSCLC in the phase III ANVIL (NCT02595944) and PEARLS (NCT02504372) trials, respectively. ANVIL is an open-label drug versus observation trial, and PEARLS compares active drug therapy versus placebo administered over 1 year.

However, a number of key issues surround the future use of these drugs in the adjuvant setting. There is still no consensus on the optimal predictive biomarker of response to these agents, and clinical benefit has been demonstrated even in patients who are deemed biomarker negative for tumor PD-L1 expression. Therefore, the study design of these adjuvant trials must be biomarker agnostic in terms of eligibility, but statistical analysis should be stratified to address the question of interaction between biomarker status and treatment outcomes. If the adjuvant trials meet their endpoints, the optimal schedule and duration of therapy must also be refined given the cost of these agents and the likelihood of clinical benefit with alternate, less-frequent dosing schedules. Additional considerations include the impact and necessity of sequencing therapy with standard platinum-based adjuvant chemotherapy in the appropriate clinical context.

Finally, although recurrence-free survival can be determined sooner in assessing efficacy, improvement in OS should still be the ultimate endpoint to justify widespread adoption of these agents as a standard in the adjuvant setting.