Efficacy and safety of nanoparticle albumin-bound paclitaxel monotherapy after immune checkpoint inhibitor administration for advanced non-small cell lung cancer: A multicenter Phase 2 clinical trial

The study addresses whether prior exposure to immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1 agents modifies the efficacy and safety of subsequent chemotherapy in advanced non-small cell lung cancer (NSCLC). While ICIs have improved overall survival despite modest objective response rates, outcomes after progression remain suboptimal, underscoring a need for effective post-ICI therapies. Nab-paclitaxel has shown favorable progression-free survival compared with docetaxel and a safety profile potentially superior to docetaxel plus ramucirumab. Additionally, chemoimmunotherapy regimens including nab-paclitaxel have been effective and well tolerated, suggesting nab-paclitaxel may be suitable immediately after ICI failure. The purpose of this multicenter Phase 2 study was to prospectively evaluate the efficacy and safety of nab-paclitaxel monotherapy administered soon after PD-(L)1 inhibitor failure in advanced NSCLC.

Prior trials demonstrated that ICIs improve OS in advanced NSCLC compared to chemotherapy, but ORRs are lower, suggesting potential post-treatment benefits. Retrospective studies have reported mixed findings regarding enhanced chemotherapy efficacy immediately after ICI, with reported ORRs ranging 18%–60%. Nab-paclitaxel has shown longer PFS versus docetaxel in previously treated NSCLC and may have fewer severe adverse events than docetaxel plus ramucirumab. Combinations of nab-paclitaxel with PD-(L)1 inhibitors (e.g., in IMpower130 and other trials) exhibited efficacy and tolerability, implying nab-paclitaxel does not exacerbate toxicities post-ICI. The literature therefore supports evaluating nab-paclitaxel as a post-ICI option but lacks prospective evidence focused on this sequence.

Design: Three-center, open-label, single-arm Phase 2 clinical trial (UMIN000030994), conducted per GCP and the Declaration of Helsinki with ethics approvals from participating institutions. Written informed consent obtained. Patients: Adults (≥20 years) with histologically/cytologically confirmed advanced or recurrent NSCLC; within 12 weeks after failure (progression or unacceptable toxicity) of PD-(L)1 inhibitor therapy (monotherapy or combination); ECOG PS 0–2; measurable disease per RECIST v1.1; adequate organ function (WBC ≥3000/mm3, ANC ≥1500/mm3, Hb ≥9.0 g/dL, platelets ≥100,000/mm3, AST/ALT ≤100 IU/L, total bilirubin ≤1.5 mg/dL, creatinine ≤1.5 mg/dL, urine protein ≤1+, PT-INR ≤1.5, room-air SpO2 ≥90%); life expectancy >3 months. Prior targeted therapy for driver mutations, radiotherapy, and chemotherapy excluding (solvent-based) paclitaxel/nab-paclitaxel permitted. Key exclusions: Severe allergy to nab-paclitaxel/albumin; prior paclitaxel/nab-paclitaxel; systemic corticosteroid >10 mg prednisolone equivalent at registration; ≥Grade 2 peripheral neuropathy; interstitial pneumonia on chest X-ray; symptomatic effusions requiring drainage; symptomatic brain metastasis; RT within 2 weeks; major surgery within 4 weeks; active second malignancy; lactation/pregnancy; HBsAg positive. Treatment: Nab-paclitaxel 100 mg/m2 IV over 30 minutes on Days 1, 8, 15 of a 28-day cycle. Cycle 2+ required ANC ≥1500/mm3, platelets ≥100,000/mm3, Hb ≥9.0 g/dL, AST/ALT ≤2.5× ULN, total bilirubin ≤1.5 mg/dL, creatinine ≤1.5 mg/dL, peripheral neuropathy ≤Grade 2. Day 8/15 dosing required ANC ≥500/mm3, platelets ≥50,000/mm3, neuropathy ≤Grade 2. Dose reductions in 20 mg/m2 steps (minimum 60 mg/m2) for specified hematologic/non-hematologic toxicities. Treatment continued until RECIST-defined progression or unacceptable toxicity. Assessments: Tumor imaging by CT or MRI every ≤8 weeks; responses per RECIST v1.1 with confirmation ≥4 weeks after initial response. Brain MRI at diagnosis; repeated during treatment for known/suspected brain metastases. Endpoints: Primary—Objective response rate (ORR) by investigator per RECIST v1.1. Secondary—Disease control rate (DCR), progression-free survival (PFS; from enrollment to progression), overall survival (OS; from enrollment to death), and safety (NCI-CTCAE v4.0). Subsets analyzed by age, sex, ECOG PS, histology, smoking history, PD-L1 expression, and number of prior regimens. Statistics: Response summarized as counts/percentages with exact 95% CIs; Fisher’s exact test for categorical associations; PFS/OS by Kaplan–Meier with 95% CIs; prognostic factors via Cox proportional hazards (stepwise). Significance at p<0.05. Sample size based on one-arm binomial test: threshold ORR 7% (docetaxel historical), expected ORR 25% (nab-paclitaxel prior data), α=0.05 (one-sided), β=0.2, yielding 24 required; 30 planned allowing ineligibility.

- Enrollment and analysis: 30 enrolled; 29 evaluable (Feb 2018–Dec 2020). Median follow-up 12.0 months (range 2.3–46.5). - Efficacy: ORR 55.2% (16/29; 95% CI 28.1%–79.6%): CR 3.4% (1/29), PR 51.7% (15/29). DCR 86.2% (25/29; 95% CI 65.9%–97.0%). Median PFS 5.6 months (95% CI 4.4–6.7); PFS at 1 and 2 years: 34.5% and 13.3%. Median OS 11.9 months (95% CI 0.8–23.0). - Subsets and predictors: No clear ORR differences by age, PS, histology, smoking, PD-L1, or prior lines; PD-L1 expression did not influence response. Cox analyses: For PFS, ECOG PS 0 (HR 0.19; 95% CI 0.06–0.57; p=0.003; multivariable HR 0.19; 95% CI 0.06–0.58; p=0.004) and being a responder to prior ICI (HR 0.36; 95% CI 0.14–0.90; p=0.028) were favorable predictors. For OS, ECOG PS 0 (HR 0.21; 95% CI 0.06–0.72; p=0.013) and prior ICI response (HR 0.25; 95% CI 0.08–0.75; p=0.014) significant in univariate; multivariable showed age <70 years (HR 0.31; 95% CI 0.11–0.89; p=0.029) and prior ICI response as independent predictors. Long-term responses (≥2 years PFS) occurred in 13.3%. - Notable subsets: All three EGFR-mutated cases responded (1 CR, 2 PR). Three patients previously treated with docetaxel+ramucirumab also achieved PR with nab-paclitaxel. - Treatment exposure: Median 6 cycles (range 1–38); dose reductions in eight patients; treatment discontinued due to AEs in four and refusal in two. - Safety: Common hematologic AEs: leukopenia 27.6% (Grade ≥3), neutropenia 31.0% (Grade ≥3); no febrile neutropenia. Common non-hematologic AEs: peripheral sensory neuropathy 41.4% (Grade ≥3: 6.9%); alopecia 58.6% (no Grade ≥3). Interstitial lung disease in 10.3% (3/29), including 3.4% Grade 3. No treatment-related deaths.

This prospective, single-arm Phase 2 trial demonstrates that nab-paclitaxel administered immediately after PD-(L)1 inhibitor failure in advanced NSCLC achieves a high ORR (55.2%) and favorable PFS (median 5.6 months), exceeding historical results of nab-paclitaxel in ICI-naïve populations and aligning with or surpassing post-ICI chemotherapy outcomes reported in retrospective series. The data suggest a potential synergistic or priming effect of prior immunotherapy on subsequent paclitaxel-based chemotherapy, with durable disease control in a subset (13.3% PFS at 2 years). Prior response to ICI and good baseline performance status predicted longer PFS and OS, consistent with the hypothesis that ongoing immunologic effects may influence subsequent chemotherapy benefit. Mechanistically, paclitaxel may modulate the tumor microenvironment (e.g., dendritic cell activation, PD-L1 upregulation, increased CD8+ infiltration), potentially complementing residual ICI effects. Safety was acceptable and comparable to nab-paclitaxel monotherapy without prior ICI exposure, though a slightly higher ILD incidence warrants attention. Overall, findings support nab-paclitaxel as a reasonable post-ICI option with meaningful activity and manageable toxicity.

Nab-paclitaxel monotherapy administered soon after PD-(L)1 inhibitor failure in advanced NSCLC produced a high objective response rate and durable responses in a subset, with an acceptable safety profile. These results suggest that prior ICI may enhance the efficacy of subsequent chemotherapy and support nab-paclitaxel as an appropriate post-ICI treatment option. Future research should include larger prospective or randomized studies to confirm benefit versus other standard regimens, evaluate biomarkers (including prior ICI response) to refine patient selection, and assess efficacy after contemporary chemoimmunotherapy first-line regimens.

- Single-arm, small sample size (n=29 evaluable), limiting precision of efficacy and safety estimates; randomized Phase 3 validation is lacking. - Only nab-paclitaxel was studied; generalizability to other chemotherapeutics is unknown. - Most patients received ICI monotherapy prior to study due to local approvals; the effectiveness of post-ICI nab-paclitaxel after chemoimmunotherapy combinations requires further confirmation. - Potentially increased incidence of ILD post-ICI requires investigation. - Three-center study with potential selection of patients having preserved performance status and organ function, which may limit generalizability.