Beyond PACIFIC: efficacy of the dual inhibition of TGF-β and PD-L1 for stage III non-small cell lung cancer concurrent chemoradiotherapy treatment

Treatment of stage III non-small cell lung cancer (NSCLC) is complex and varies depending on the size of the primary tumor, the presence of lymph node metastases, and invasion into surrounding tissues. Multidisciplinary treatment, including surgery, radiation, and chemotherapy, is frequently administered and the choice of treatment is determined by a consensus of internal oncological, surgical, and radiological specialist recommendations. Recently, the results of the CheckMate-816, IMpower-010, ADAURA, AEGEAN, KEYNOTE-671, and PEARLS trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs) and molecular targeted therapies as perioperative therapy for stage III NSCLC (1-7). On the other hand, when surgery is not possible, chemoradiotherapy (CRT) is considered. The results of the PACIFIC trial have already demonstrated the efficacy of durvalumab combined with concurrent chemoradiotherapy (cCRT) and is widely used for the treatment of inoperable patients (8,9). One possible mechanism for the use of durvalumab is its synergistic efficacy with radiotherapy on the abscopal effect (10,11). However, 15–30% of patients may not be eligible to receive consolidation durvalumab therapy because of disease progression during or immediately after cCRT, radiation pneumonitis, or other adverse events (AEs). The PACIFIC-2 trial of concurrent durvalumab plus CRT followed by consolidation durvalumab in patients with unresectable stage III NSCLC as an alternative to the PACIFIC regimen was recently reported, but it did not achieve statistical significance for the primary endpoint of progression-free survival (PFS) compared with CRT alone for unresectable, stage III NSCLC (12). Thus, the development of new therapies using cCRT beyond the PACIFIC regimen is ongoing.

The treatment of NSCLC with ICIs has shown significant efficacy for tumors with high levels of programmed death-ligand 1 (PD-L1) expression (8,9,13); however, the activity of transcription growth factor-β (TGF-β) affects resistance to ICIs (14). Therefore, bintrafusp alfa (BA), a dual inhibitor that simultaneously targets TGF-β and PD-L1, was developed. BA has excellent efficacy against immunogenic tumors (15) and several clinical trials are currently underway. ICIs have shown limited efficacy in “cold tumors” with low PD-L1 expression and a low number of reactive lymphocytes; however, immune repriming with radiotherapy can convert cold tumors to hot tumors and improve the efficacy of ICIs. This is one mechanism underlying the efficacy of the PACIFIC regimen of cCRT followed by durvalumab maintenance therapy (16,17). On the other hand, the efficacy of these radiotherapy may be offset by evasive mechanisms in the tumor microenvironment, including the induction of angiogenesis and fibrotic growth factors through TGF-β induction (18). Therefore, the combination of radiotherapy with immune checkpoint and TGF-β inhibitors may be effective for the treatment of these cold tumors. Lan et al. reported the efficacy of the combination of radiotherapy and BA in cold tumors in vitro and in vivo studies (19). They showed that BA combined with radiotherapy (BART) enhanced antitumor activity in a mouse tumor model with low levels of tumor-infiltrating lymphocytes. BART suppressed tumor growth and prolonged survival in their tumor model, which indicated that the simultaneous inhibition of TGF-β and PD-L1 is an effective immunotherapy for tumors with low immune infiltration. Furthermore, the inhibition of TGF-β by BA also suggested the possibility of radiotherapy-induced fibrosis in mouse lungs.

In 2024, Vokes et al. (20) reported the results of a randomized phase II trial comparing BA combined with cCRT followed by BA (n=75) with placebo combined with cCRT followed by durvalumab (n=78) in 153 randomized patients with unresectable stage III NSCLC (20). Radiotherapy was administered concurrently with 30 fractions of platinum-doublet chemotherapy (60 Gy). BA (1,200 mg) was administered every 2 weeks for both cCRT and maintenance therapy, whereas durvalumab (10 mg/kg) was administered every 2 weeks for maintenance therapy only in the placebo group. The primary objective was the evaluation of PFS based on the Response evaluation criteria in solid tumors version 1.1. The study included a safety run-in phase and an expansion phase, with the former stratifying patients according to ethnicity (Japanese or non-Japanese) and the latter stratifying patients according to chemotherapy regimen and PD-L1. Because tumor histologic diagnosis was not stratified, the proportion of patients with adenocarcinoma was significantly higher in the BA group (61.3%) compared with that in the durvalumab group (39.7%). The primary endpoint, median PFS, was 12.8 months [95% confidence interval (CI): 7.5 to not estimable (NE)] in the BA group compared with 14.6 months (95% CI: 7.3 to NE) in the durvalumab group [stratified hazard ratio (HR): 1.48; 95% CI: 0.69–3.17]. The percentage of stage IIIA patients in the BA group was higher (45.3%) compared with that of the durvalumab group (39.7%). As a result, the BA group failed to demonstrate its usefulness. The median duration of treatment with BA and durvalumab was 12.6 (range, 2.0–64.1) and 16.3 (range, 2.0–76.4) weeks, respectively. Compared with the BA group, a PFS benefit was observed in most subgroups of the durvalumab cohort. Subgroup analysis by PD-L1 expression (SP263 assay) for 1% was 9.0 months with BA and NE with durvalumab (HR 0.86; 95% CI: 0.28–2.64), and ≥1% was NE with BA and 12.8 months with durvalumab (HR 1.25; 95% CI: 0.53–2.93). The objective response rate was 29.3% in the BA group compared with 32.1% in the durvalumab group. Median overall survival (OS) could not be evaluated by the Kaplan-Meier method in either group (stratified HR 3.28; 95% CI: 1.15–9.38). The most common treatment-emergent adverse events (TEAEs; any-grade, ≥30%) in the BA and durvalumab groups were anemia (51.4% vs. 41.6%, respectively), constipation (31.1% vs. 44.2%), nausea (36.5% vs. 39.0%), esophagitis (20.3% vs. 31.2%), and decreased white blood cell count (32.4% vs. 37.7%). The rate of TEAEs resulting in death was higher in the BA (10.8%) group compared with that in the durvalumab group (3.9%). The proportion of patients with TEAEs of grade 3 or higher resulting from immunotherapy (32.4% vs. 15.6%), radiotherapy (35.1% vs. 27.3%), and chemotherapy (64.9% vs. 49.4%) was higher in the BA compared with that in the durvalumab group, respectively. The most common any-grade AEs (>10%) observed with radiotherapy in the BA and durvalumab groups were esophagitis (18.9% vs. 29.9%, respectively), anemia (17.6% vs. 13.0%), radiation esophagitis (16.2% vs. 13.0%), decreased neutrophil count (10.8% vs. 15.6%), and neutropenia (10.8% vs. 3.9%). The proportion of patients with AEs (>1%) occurring immediately after radiotherapy in the BA and durvalumab groups was 8.1% and 5.2%, respectively. The most common late-onset AEs (>10%) after radiotherapy in the BA and durvalumab groups were anemia (13.5% vs. 9.1%) and febrile neutropenia (10.8% vs. 9.1%), respectively. The proportions of bleeding events in the BA group were mostly grade 1 (21.6%) and grade 2 (9.5%). Grade 3 and 5 bleeding events were observed in 6.8% and 2.7% of the cases, respectively. Overall, 17.6% of patients in the BA group died, with the majority of deaths (6.8%) due to progression of the underlying disease and disease-related conditions, compared with 6.5% in the durvalumab group. Fewer deaths occurred within 60 days after the initiation of treatment in the durvalumab arm compared with that in the BA arm (2.6% vs. 4.1%, respectively). Finally, based on a review of the cumulative data of these 153 randomized participants and the total efficacy and safety data available until the data cutoff date, which was conducted by the Independent Data Monitoring Committee, it was recommended that the study be discontinued because of the unfavorable risk-to-benefit ratio and the low probability of achieving the proposed efficacy endpoints. Thus, the study was discontinued before the OS data reached maturity. At the time the study was discontinued, the PFS and OS outcomes were less favorable for the BA group compared with that for the durvalumab group.

Based on these results, the PACIFIC regimen, cCRT following durvalumab administration, remains the standard treatment for inoperable stage III NSCLC. However, some patients will relapse during the course of cCRT or will not recover from cCRT. Although the BART trial and PACIFIC-2 trial for stage III NSCLC failed to achieve the primary endpoint, further studies are needed to determine whether concurrent immunotherapy with cCRT is effective. Currently, several phase III studies are ongoing to evaluate new strategies to improve survival compared with the PACIFIC study: adjuvant combination immunotherapy after cCRT or concurrent immunotherapy with cCRT (Table 1).

The results of a randomized phase III trial of single-agent pembrolizumab vs. BA in patients with advanced NSCLC and PD-L1 levels ≥50% indicated that PFS, the primary endpoint, was 7.0 months in the BA arm (95% CI: 4.2 to not reached) versus 11.1 months in the pembrolizumab arm (95% CI: 8.1 to not reached), whereas the HR for PFS was 1.232 (95% CI: 0.885–1.714). Therefore, the study was discontinued before the accrual of the protocol-defined number of OS events required for the primary analysis (21). The results of this study failed to show an advantage of BA as first-line therapy in patients with advanced NSCLC accompanied by high PD-L1 expression levels versus pembrolizumab in terms of efficacy. Higher AE rates were observed in the BA group compared with that in the pembrolizumab arm. In addition, compared with patients receiving pembrolizumab, a higher rate of those treated with BA developed AEs resulting in permanent or temporary treatment discontinuation. TGF-β inhibition-mediated skin AEs, bleeding, and anemia were more common in patients receiving BA compared with those receiving pembrolizumab. By contrast, drug-induced pneumonia was observed in 3.3% of the patients receiving pembrolizumab compared with 0% of those receiving BA. The reason no improvement in efficacy compared with pembrolizumab was observed in the present study may be associated with the pleiotropic nature of TGF-β signaling, which contributes to drug resistance and tumor escape, thereby weakening the clinical response and antitumor effect of anti-PD-L1 therapy (22). Besides, more AEs occurred in the BA group, which resulted in a higher rate of patients with temporary or permanent treatment discontinuation, may have reduced efficacy compared with pembrolizumab. These results make it difficult to expect greater efficacy over pembrolizumab with BA, at least in patients with advanced NSCLC with PD-L1 ≥50%. This may be the result of the TGF-β inhibitory effect of BA, which may interfere with the efficacy of the PD-L1 antibody itself, as well as the inherent side effects of TGF-β inhibition, such as a tendency for bleeding. Subgroup analysis by PD-L1 expression was also performed in the current study, but details were not available because of the study’s discontinuation. For the use of BA and CRT in combination or BA alone for the treatment of NSCLC, it may be necessary to target populations with low PD-L1. This is consistent with the original concept predicting the efficacy of TGF-β inhibition over PD-L1 inhibition in cold tumors. In addition, a biomarker analysis of BA was performed in stage IIIb/IV NSCLC patients with ICI-naïve or ICI-treated (23). Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment tumor biopsies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment may be linked with clinical response. The discovery of novel biomarkers, including these, may support the use of BA.

In conclusion, this examination of stage III NSCLC treatment underscores the complexity and evolving nature of therapeutic strategies. While the PACIFIC regimen with durvalumab remains the current standard for inoperable locally advanced stage III lung cancer, the study of BA in combination with cCRT has raised important considerations. The outcomes highlight the challenges associated with concurrent immunotherapy and CRT and emphasize the difficulties in developing new treatments. The higher proportion of AEs observed with BA and the potential interference of TGF-β inhibition with PD-L1 antibody efficacy underscores the need for precision in patient selection. The combined effect of TGF-β and PD-L1 inhibition for the treatment of NSCLC remains unclear and it will take at least some ingenuity, including the search for new biomarkers, to establish its value.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-16/coif). T.U. reports receiving payment or honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Japan, Kyowa Kirin, MSD, Novartis Pharma, and Taiho. The author has no other conflicts of interest to declare.

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