Introduction: The Evolving Landscape of Neoadjuvant Therapy in NSCLC
The management of resectable non-small cell lung cancer (NSCLC) has undergone a tectonic shift over the last five years. Historically, the five-year survival rate for patients with early-stage NSCLC remained suboptimal despite successful surgical resection, primarily due to high rates of systemic recurrence. The advent of neoadjuvant immunotherapy, particularly when combined with platinum-based chemotherapy, has redefined clinical expectations. Trials such as CheckMate 816 have demonstrated that achieving a major pathologic response (MPR) or a pathologic complete response (pCR) serves as a robust surrogate for improved event-free survival (EFS) and overall survival (OS). However, while chemo-immunotherapy has set a new baseline, researchers continue to explore more potent combinations to maximize the depth of response and address patients who may not tolerate intensive chemotherapy. The ALTER-L043 trial, a multicenter, randomized, phase II study, enters this arena by investigating the synergy of PD-1 inhibition, multi-kinase anti-angiogenesis, and chemotherapy.
Highlighting the Success of ALTER-L043
Published in Signal Transduction and Targeted Therapy, the ALTER-L043 trial (NCT04846634) provides compelling evidence for the use of penpulimab—a programmed cell death protein 1 (PD-1) inhibitor—in combination with anlotinib, a multi-target tyrosine kinase inhibitor (TKI) that inhibits VEGFR, FGFR, PDGFR, and c-Kit. The study’s most striking finding is the 76% MPR rate observed in the triplet therapy arm (penpulimab plus anlotinib and chemotherapy). This figure significantly outperforms historical benchmarks for neoadjuvant chemo-immunotherapy alone, which typically hover between 30% and 45% for MPR. Furthermore, the trial provides a critical look at a chemo-free neoadjuvant option, which achieved an MPR of over 50%, offering a potential lifeline for patients with poor performance status or contraindications to cytotoxic agents.
Study Design and Patient Selection
The ALTER-L043 trial was designed as an open-label, multicenter, randomized, phase II study to evaluate the efficacy and safety of different penpulimab-based perioperative regimens. Between late 2021 and early 2024, 90 patients with resectable NSCLC were enrolled and randomly assigned in a 1:1:1 ratio to one of three intervention arms:
Arm A: The Triplet Regimen
Patients received 3 to 4 cycles of neoadjuvant penpulimab (200 mg, day 1), anlotinib (12 mg, days 1-14), and platinum-doublet chemotherapy. This was followed by surgery and matching adjuvant therapy.
Arm B: Chemo-Immunotherapy
Patients received penpulimab (200 mg) and platinum-doublet chemotherapy, serving as a standard-of-care comparator within the trial context.
Arm C: The Chemo-Free Regimen
Patients received penpulimab (200 mg) and anlotinib (12 mg), exploring the potential of dual targeted and immune therapy without the toxicity of chemotherapy.
The primary endpoint was the investigator-assessed MPR rate among patients who underwent definitive surgery. Secondary endpoints included pCR rates, surgical feasibility, and safety profiles across all phases of treatment.
Efficacy Outcomes: A New Benchmark for MPR and pCR?
The results of the ALTER-L043 trial underscore the potent clinical activity of the triplet combination. Among the 30 patients in each group, the surgical rates varied significantly. In the triplet arm (Arm A), 92.6% of patients underwent definitive surgery. In Arm B, the rate was 89.7%, while in the chemo-free Arm C, the rate dropped to 70.0%.
The Dominance of the Triplet Regimen
In Arm A, the pathological response data were exceptional. Among those who underwent surgery, the MPR rate reached 76.0% (95% CI 54.9–90.6), and the pCR rate was 52.0% (95% CI 31.3–72.2). These results suggest that the addition of anlotinib to a chemo-immunotherapy backbone creates a highly hostile environment for the tumor, leading to unprecedented levels of pathological clearance before the surgeon even makes the first incision.
The Standard and Chemo-Free Alternatives
Arm B (penpulimab plus chemotherapy) showed an MPR of 57.7% and a pCR of 50.0%, which is consistent with, or slightly higher than, other phase II and III studies of similar combinations. Most interestingly, Arm C (chemo-free) achieved an MPR of 52.4% and a pCR of 38.1%. While the surgery rate was lower in this group, the depth of response in those who did reach the operating room suggests that anlotinib and penpulimab alone have significant anti-tumor activity.
Safety and Surgical Feasibility
A critical concern in neoadjuvant trials is whether the intensity of the regimen will lead to treatment-related adverse events (TRAEs) that delay or prevent surgery. In ALTER-L043, the incidence of grade 3 or higher TRAEs was 26.7% in the triplet arm, 20.0% in the chemo-immunotherapy arm, and 30.0% in the chemo-free arm. The slightly higher toxicity in the chemo-free arm was largely attributed to anlotinib-specific effects, such as hypertension or hand-foot syndrome, rather than immune-related events.
Crucially, the triplet therapy did not appear to increase surgical complexity or postoperative complications compared to the other arms. The high rate of definitive surgery (92.6%) in Arm A confirms that the addition of a multi-kinase inhibitor to the neoadjuvant mix is feasible and does not result in prohibitive tissue friability or vascular complications, which are often concerns with anti-angiogenic agents.
Expert Commentary: Mechanistic Synergy and Clinical Translation
The high efficacy of the penpulimab-anlotinib-chemotherapy triplet can be explained through several biological mechanisms. Anti-angiogenic agents like anlotinib do more than just starve the tumor of blood; at appropriate doses, they promote ‘vascular normalization.’ In a normal tumor, blood vessels are chaotic and leaky, creating high interstitial fluid pressure that prevents both chemotherapy drugs and immune cells from penetrating the tumor core. By normalizing these vessels, anlotinib may improve the delivery of chemotherapy and the infiltration of CD8+ T cells activated by penpulimab.
Furthermore, penpulimab is a unique PD-1 inhibitor. It is engineered as an IgG1 variant that eliminates Fc-gamma receptor binding, thereby reducing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of T cells. This allows for a more sustained and effective immune response against the tumor compared to some traditional PD-1 inhibitors.
However, we must remain cautious. The lower surgery rate in the chemo-free arm (70%) suggests that without chemotherapy, some tumors may not be sufficiently downstaged, or disease progression may occur in the neoadjuvant window. For the majority of fit patients, the triplet remains the most robust option, while the chemo-free regimen requires further refinement to identify which specific biomarkers (such as PD-L1 expression or TMB) might predict success.
Conclusion
The ALTER-L043 trial represents a significant step forward in the quest for more effective perioperative treatments for NSCLC. By demonstrating that a triplet regimen of penpulimab, anlotinib, and chemotherapy can achieve an MPR of 76%, the study sets a high bar for future phase III trials. For clinicians, these results provide strong evidence that incorporating anti-angiogenesis into neoadjuvant protocols is not only safe but potentially transformative for patient outcomes. As we await long-term survival data, the pathological response rates seen here offer substantial hope for reducing recurrence and improving the lives of patients with resectable lung cancer.
Funding and Trial Registration
This study was supported by various national health research funds and Chia Tai Tianqing Pharmaceutical Group. The trial is registered at ClinicalTrials.gov under the identifier NCT04846634.
References
1. Wang M, Liu W, Guo H, et al. Perioperative penpulimab-based combination therapy in patients with resectable non-small cell lung cancer (ALTER-L043): an open-label, multicenter, randomized, phase II trial. Signal Transduct Target Ther. 2026;11(1):21. doi:10.1038/s41392-025-02544-w.
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170.
3. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389(13):1165-1177. doi:10.1056/NEJMoa2304875.
