Baseline Response Rates Inform Immunotherapy Sequencing in NSCLC

For patients who have non–small cell lung cancer (NSCLC) and have received immunotherapy with an immune checkpoint inhibitor (ICI), the investigators of a new study suggest that a baseline response rate of 10% could be used to gauge the ongoing effectiveness of novel ICI treatment combinations. Their investigation compared outcomes among 3 cohorts of patients who received the PD-L1 inhibitor atezolizumab every 3 weeks at 1200 mg after treatment failure with PD-1 inhibitors nivolumab or pembrolizumab, and they published their findings in Clinical Lung Cancer.¹

This investigator-initiated single-arm phase 2 clinical trial enrolled patients between August 2017 and April 2021 who had stage IIIB/IV NSCLC and who were previously treated with nivolumab (42.9%) or pembrolizumab (57.1%). Their median age was 74 (range, 48-87) years, 85.7% reported a White race, 53.6% were female patients, 64.3% each had an ECOG performance status and were former smokers, and median lines of prior treatment were 2 (range, 1-6). The most common disease histology was adenocarcinoma (85.7%), and patients were placed into 1 of 3 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 12 weeks of treatment
• Cohort 3 (n = 8): partial (PR) or complete response (CR) followed by PD

Disease response was evaluated every 6 weeks using RECIST v1.1 criteria. The primary outcome was best overall response, and secondary outcomes were duration of response, progression-free survival (PFS), overall survival (OS), and safety. “A stopping rule for futility was implemented using Simon’s optimal 2-stage design,” the authors wrote, “if none of the first 1 evaluable patients within a cohort had confirmed objective response.” Under this method of study evaluation, a phase 2 clinical trial will proceed to its second stage unless the null hypothesis—that no statistical significance is evident between study groups²—is met.³

In this analysis, the study authors wanted a greater understanding of optimal sequencing of the immune checkpoint inhibitor atezolizumab. | Image Credit: © kentoh-stock.adobe.com

The most common tumor cell (TC) and immune cell (IC) scores via immunohistochemistry were TC1/2/3 or IC1/2/3 and TC0/IC0 in 17.9% of those who received a PD-L1 prior to nivolumab or pembrolizumab and 32.1% and 17.9%, respectively, in those who received a PD-L1 prior to atezolizumab.

Overall, 85.7% of entire study population completed cycle 2 of therapy and had at least 1 radiographic scan. In cohort 1, there were 2 PRs of 3 months and 9 months (11.8%; 95% CI, 1.5%-36.4%), 4 cases of SD (23.5%; 95% CI, 6.8%-49.9%), 8 cases of PD (47.1%; 95% CI, 23.0%-72.2%), and 3 patients of unknown status due to lack of subsequent imaging. Responses were not evident in any of the patients in cohort 2; there were 2 cases of PD (66.7%; 95%CI, 9.4%-99.2%) and 1 of SD (33.3%; 95% CI, 0.8%-90.6%). Among those placed in cohort 3, there was only 1 PR (12.5%; 95% CI, 0.3%-52.7%), 4 cases of SD (50.0%; 95% CI, 15.7%-84.3%), 2 cases of PD (25.0%; 95% CI, 3.3%-65.1%), and 1 patient who did not have subsequent imaging.

For cohorts 1 and 3, the 6-week disease control rates came in at 53.3% (95% CI, 26.6%-61.3%) and 100.0% (95% CI, 29.2%-100.0%), respectively; at 12 weeks, the corresponding rates were 26.7% (95% CI, 7.8%-55.1%) and 71.4% (95% CI, 29.0%-96.3%).

Median PFS was 2 months in cohorts 1 and 2, and 4 months in cohort 3. OS for each was 6 months, 11 months, and 7.5 months, respectively.

More than half of the overall study population (57.1%) experienced an any-grade treatment-related adverse event (TRAE), with fatigue most common (68.8%). There were also 4 TRAEs of at least grade 3, with 1 case each of generalized muscle weakness without myositis, diarrhea, and fatigue, and 1 case of grade 4 pancreatitis.

Unfortunately, the authors of this investigation had to close their cohorts prematurely due to lack of patient accrual—but not before they saw response rates from atezolizumab of 11.8% among the patients with PD and 12.5% among those with a PR or CR who were treated with nivolumab and pembrolizumab. They also note that their PFS and OS findings were modest at best.

“Durable responses and disease control noted in patients with both primary and secondary resistance to PD-1 therapy could signal a possible benefit of sequencing anti–PD-L1 therapy after progression on anti-PD-1 therapy,” the authors concluded. “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.”

There are 2 potential limitations on these findings. The authors were unable to complete a correlative biomarker analysis due to lack of available tumor tissue, so that many of the tumors in their study had unknown PD-L1 status. Also, their study period came before primary resistance, or PD or SD lasting less than 6 months after at least 2 cycles of ICI therapy, and secondary resistance, or initial benefit of at least 6 months of an immunotherapy combination followed by PD, had been well defined in the literature.⁴

References

1. Fortman D, Wang H, VanderWeele R, et al. Brief report: phase II clinical trial of atezolizumab in advanced nonsmall cell lung cancer patients previously treated with PD-1-directed therapy. Clin Lung Cancer. 2024:S1525-7304(24)00231-6. doi:10.1016/j.cllc.2024.10.014

2. Mander AP, Thompson SG. Two-stage designs optimal under the alternative hypothesis for phase II cancer clinical trials. Contemp Clin Trials. 2010;31(6):572-578. doi:10.1016/j.cct.2010.07.008

3. Turney S. Null & alternative hypotheses | definitions, templates & examples. Scribbr. May 6, 2022. Updated June 22, 2023. Accessed December 1, 2024. https://www.scribbr.com/statistics/null-and-alternative-hypotheses/

4. Kluger H, Barrett JC, Gainor JF, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors. J Immunother Cancer. 2023;11(3):e005921. doi:10.1136/ jitc-2022-005921