Atezolizumab, a PD-L1 inhibitor, has demonstrated potential efficacy in non-small cell lung cancer (NSCLC) patients who have previously failed treatment with PD-1 inhibitors such as nivolumab or pembrolizumab. A phase 2 clinical trial, published in Clinical Lung Cancer, explored the sequencing of immune checkpoint inhibitors, suggesting that a baseline response rate of approximately 10% could indicate ongoing checkpoint inhibition against which novel combinations should be measured in the immunotherapy-experienced NSCLC population.
The investigator-initiated, single-arm phase 2 trial enrolled patients with stage IIIB/IV NSCLC who had previously been treated with either nivolumab (42.9%) or pembrolizumab (57.1%) between August 2017 and April 2021. The median age of participants was 74 years, with the majority being White (85.7%) and female (53.6%). The most common disease histology was adenocarcinoma (85.7%). Patients were categorized into three cohorts based on their best response to prior anti-PD-1 therapy:
- Cohort 1 (n = 17): Progressive disease (PD)
- Cohort 2 (n = 3): Stable disease (SD) after a minimum of 12 weeks of treatment
- Cohort 3 (n = 8): Partial (PR) or complete response (CR) followed by PD
Disease response was evaluated every six weeks using RECIST v1.1 criteria. The primary outcome was best overall response, while secondary outcomes included duration of response, progression-free survival (PFS), overall survival (OS), and safety. A stopping rule for futility was implemented, halting further evaluation if none of the first evaluable patients within a cohort had a confirmed objective response.
Efficacy and Outcomes
Overall, 85.7% of the study population completed cycle 2 of therapy and had at least one radiographic scan. In cohort 1, two patients achieved a PR (11.8%; 95% CI, 1.5%-36.4%), with durations of 3 and 9 months, respectively. Four patients experienced SD (23.5%; 95% CI, 6.8%-49.9%), and eight had PD (47.1%; 95% CI, 23.0%-72.2%). No responses were observed in cohort 2, with two patients experiencing PD (66.7%; 95%CI, 9.4%-99.2%) and one SD (33.3%; 95% CI, 0.8%-90.6%). In cohort 3, one patient achieved a PR (12.5%; 95% CI, 0.3%-52.7%), four had SD (50.0%; 95% CI, 15.7%-84.3%), and two had PD (25.0%; 95% CI, 3.3%-65.1%).
The 6-week disease control rates for cohorts 1 and 3 were 53.3% (95% CI, 26.6%-61.3%) and 100.0% (95% CI, 29.2%-100.0%), respectively. At 12 weeks, these rates were 26.7% (95% CI, 7.8%-55.1%) and 71.4% (95% CI, 29.0%-96.3%).
The median PFS was 2 months in cohorts 1 and 2, and 4 months in cohort 3. The OS was 6 months, 11 months, and 7.5 months for cohorts 1, 2, and 3, respectively.
Safety Profile
More than half of the study population (57.1%) experienced a treatment-related adverse event (TRAE) of any grade, with fatigue being the most common (68.8%). Four TRAEs of at least grade 3 were reported, including one case each of generalized muscle weakness without myositis, diarrhea, fatigue, and one case of grade 4 pancreatitis.
Study Limitations and Conclusions
The study was limited by premature closure due to lack of patient accrual and the inability to perform a correlative biomarker analysis due to a lack of available tumor tissue. The authors noted that the study period predated the well-defined classifications of primary and secondary resistance to immunotherapy combinations.
Despite these limitations, the authors concluded that the durable responses and disease control observed in patients with both primary and secondary resistance to PD-1 therapy suggest a potential benefit of sequencing anti-PD-L1 therapy after progression on anti-PD-1 therapy. "Based on the data in the current study, a response rate of about 10% suggests a baseline activity of ongoing checkpoint inhibition against which novel combinations should be measured in the immunotherapy experienced NSCLC population," they stated.
