Lung cancer remains a leading cause of cancer-related death globally. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) like PD-1 and PD-L1 inhibitors, has improved outcomes for advanced NSCLC, but second-line treatment efficacy remains suboptimal. While some retrospective studies suggested that chemotherapy after ICI administration may enhance efficacy, others showed no such benefit, leaving the question unresolved. Nab-paclitaxel has demonstrated superior PFS compared to docetaxel and may be a safer alternative to docetaxel plus ramucirumab in second-line settings. Furthermore, the combination of nab-paclitaxel and carboplatin with a PD-(L)1 inhibitor has shown effectiveness and tolerability, suggesting potential for nab-paclitaxel monotherapy after ICI failure. This Phase 2 study aimed to prospectively evaluate the efficacy and safety of nab-paclitaxel monotherapy following PD-(L)1 inhibitor treatment failure in advanced NSCLC patients.

The literature surrounding the efficacy of chemotherapy following immunotherapy in NSCLC is mixed. Several retrospective studies reported improved efficacy of subsequent chemotherapy after ICI treatment, with varying objective response rates (ORRs) ranging from 18% to 60%. However, these studies involved diverse patient populations, various chemotherapeutic agents, and methodological limitations, hindering definitive conclusions. Conversely, some studies reported no significant enhancement of chemotherapy efficacy following immunotherapy. The existing data underscore the need for a prospective, controlled study to clarify the relationship between immunotherapy and subsequent chemotherapy response in NSCLC patients specifically using nab-paclitaxel.

This was a three-center, open-label, single-group, Phase 2 study. Patients with advanced or recurrent NSCLC, within 12 weeks of PD-(L)1 inhibitor treatment failure (due to disease progression or intolerable adverse events), ECOG performance status (PS) 0-2, and measurable lesions by RECIST v1.1 were eligible. Patients received nab-paclitaxel (100 mg/m²) intravenously on days 1, 8, and 15 of a 28-day cycle. Dose reductions were allowed for specific toxicities. Treatment continued until progressive disease (PD) or unacceptable toxicity. The primary endpoint was ORR; secondary endpoints included DCR, PFS, OS, and safety. Disease assessments were performed using CT or MRI scans. Adverse events were graded using NCI CTCAE v4.0. Statistical analyses included exact 95% CIs, Fisher's exact test, Kaplan-Meier method, and Cox proportional hazards models. The sample size was calculated based on a comparison with docetaxel, considering the expected ORR difference.

Thirty patients were enrolled, with 29 included in the analysis. The ORR was 55.2% (95% CI: 28.1%-79.6%), and the DCR was 86.2% (95% CI: 65.9%-97.0%). Median PFS was 5.6 months (95% CI: 4.4-6.7 months), with 1- and 2-year PFS rates of 34.5% and 13.3%, respectively. Median OS was 11.9 months (95% CI: 0.8-23.0 months). Univariate and multivariate analyses identified ECOG PS 0 and response to prior ICI therapy as independent predictors of longer PFS. ECOG PS 0 and age (<70 years) were independent predictors of longer OS. Grade 3 or higher toxicities included leukopenia (27.6%), neutropenia (31.0%), peripheral sensory neuropathy (6.9%), and interstitial lung disease (ILD) (3.4%). There were no treatment-related deaths. The median number of treatment cycles was 6 (range: 1-38).

This study demonstrates a higher-than-expected ORR with nab-paclitaxel monotherapy after PD-(L)1 inhibitor failure in advanced NSCLC, suggesting potential synergy between ICI and subsequent chemotherapy. The observed ORR (55.2%) is among the highest reported in similar settings, possibly due to the prospective design and selection of patients with preserved performance status and organ function. The longer PFS observed compared to previous studies using nab-paclitaxel alone might be attributed to the priming effect of prior ICI. The finding that prior response to ICI predicted longer PFS and OS on nab-paclitaxel suggests a potential selection bias and indicates the importance of considering prior treatment response. The acceptable toxicity profile further supports the clinical viability of this treatment strategy. While the increased incidence of ILD should be monitored, the overall safety profile remains comparable to nab-paclitaxel monotherapy without prior ICI.

This prospective Phase 2 study provides evidence for the efficacy and acceptable safety of nab-paclitaxel monotherapy following ICI failure in advanced NSCLC. The high ORR and durable responses observed suggest a potential synergistic interaction between ICI and subsequent nab-paclitaxel treatment. Future research should focus on a larger, randomized Phase 3 trial to confirm these findings and explore the mechanism underlying the observed synergy. Further investigation into the relationship between prior ICI response and subsequent chemotherapy outcomes is also warranted.

The relatively small sample size limits the generalizability of the findings and the precision of survival estimates. The study was conducted in a Japanese population and may not be fully generalizable to other populations. The limited number of patients receiving chemoimmunotherapy as pretreatment prevents definitive conclusions about the efficacy of nab-paclitaxel after chemoimmunotherapy. The open-label design could introduce bias, and a placebo-controlled trial would provide stronger evidence.