Immunotherapy plus targeted drug shows promise in rare aggressive lung cancer

A rare and notoriously stubborn form of lung cancer may have a new first-line treatment option.

Treatment continued until disease progression or unacceptable side effects.

The results were striking for a disease with such a poor track record. Twelve of the 28 patients, or 42.9 percent, achieved a confirmed partial response, comfortably exceeding the 35 percent response rate the investigators had set as their target when designing the study. No complete responses were recorded, but another 12 patients had stable disease, bringing the disease control rate to 85.7 percent. Among those who responded, the median duration of response reached 16 months, suggesting that for some patients the benefit is durable rather than fleeting.

Survival outcomes also outpaced historical expectations. Patients with advanced pulmonary sarcomatoid carcinoma treated with conventional chemotherapy typically survive only 4.3 to 7.9 months. In this trial, the median progression-free survival was 7.1 months and the median overall survival was 18.1 months, with 85.7 percent of patients alive at six months and more than half still alive at 18 months. Notably, 24 of the 27 patients with evaluable tumor assessments showed a measurable shrinkage of their target lesions from baseline, indicating broad biological activity of the combination even in patients who did not meet the formal criteria for a response.

The scientific rationale behind the combination is rooted in the peculiar biology of this tumor type. Pulmonary sarcomatoid carcinoma contains both carcinomatous and sarcomatous components and tends to display high levels of PD-L1, the molecular target that immune checkpoint inhibitors exploit, along with a T-cell inflamed tumor microenvironment. But high PD-L1 expression in these tumors is frequently accompanied by overexpression of hypoxia-inducible factor-1 alpha, a protein that drives production of vascular endothelial growth factor A and fuels the formation of new blood vessels that feed the tumor. The receptor PDGFR-beta, another promoter of angiogenesis, is also upregulated. Pairing a PD-1 blocker with an antiangiogenic agent is therefore designed to attack both the immune evasion machinery and the vascular supply simultaneously.

Before CAPSTONE, prospective evidence for this approach was almost nonexistent. Prior phase 2 trials had tested durvalumab combined with tremelimumab or with chemotherapy agents in this population, and retrospective analyses suggested that adding antiangiogenic therapy to immunotherapy improved outcomes, with one study reporting a higher response rate and longer progression-free survival. But no prospective trial had directly evaluated an immune checkpoint inhibitor plus an antiangiogenic drug as first-line therapy for pulmonary sarcomatoid carcinoma. CAPSTONE is, according to its investigators, the first multi-center phase 2 trial to do so.

Safety data were broadly consistent with the known profiles of both drugs. Nearly all patients, 96.4 percent, experienced at least one treatment-related adverse event, with the most common being proteinuria, hypertension, decreased neutrophil count, decreased platelet count and elevated liver enzymes. Serious grade 3 or worse events occurred in 35.7 percent of patients, most frequently involving low platelet and neutrophil counts. Dose interruptions of famitinib were required in more than half of patients, and a small number discontinued one or both drugs because of toxicity. Immune-related side effects, such as elevated liver enzymes and hypothyroidism, appeared in 39.3 percent of patients but were mostly mild.

Two deaths cast a shadow over the otherwise encouraging safety picture. Two male patients with very large baseline tumor burdens, measuring 135 and 236 millimeters in target lesion diameter, developed grade 4 thrombocytopenia after one or two cycles of treatment and died 29 and 40 days after starting therapy. The cause of death could not be determined in either case because no autopsy was performed. The investigators judged both deaths as possibly related to study treatment, noting that while advanced disease and heavy tumor burden meant disease progression could not be excluded, the temporal relationship between treatment exposure, the severe blood cell decline and death meant a treatment-related contribution could not be ruled out either.

An exploratory analysis added a layer of molecular insight. Single-cell RNA sequencing of pretreatment tumor samples from seven patients, covering more than 73,000 individual cells, revealed differences in T-cell composition between patients who lived longer without progression and those who did not. Patients with longer progression-free survival showed CD8 T cells with higher expression of genes associated with T-cell activation and proliferation, including PDCD1, IFNG and MKI67. The proportions of particular CD4 and CD8 T-cell subpopulations, labeled cluster 0, showed an inverse association with the change in target lesion size during treatment. Genomic sequencing of 26 patients identified frequent mutations in TP53, EGFR, KRAS and PTEN, consistent with prior reports, although neither tumor mutational burden nor neoantigen burden correlated significantly with survival in this small cohort.

The investigators are careful to frame these findings as preliminary rather than practice-changing. The study was single-arm, meaning there was no control group, and the small sample size produced wide confidence intervals around every efficacy estimate. Patient recruitment was uneven across centers, more than a quarter of patients had unknown PD-L1 status because of insufficient tissue, and the single-cell analysis involved only seven participants, making the biomarker findings hypothesis-generating at best. Because pulmonary sarcomatoid carcinoma is so rare, no phase 3 trial has ever been conducted for this disease, and the authors call for larger randomized controlled studies to confirm the activity of camrelizumab plus famitinib and to determine how much of the benefit comes from famitinib itself.

Subject of Research: First-line camrelizumab plus famitinib for advanced pulmonary sarcomatoid carcinoma

Article Title: Camrelizumab plus famitinib as first-line treatment for locally advanced or metastatic pulmonary sarcomatoid carcinomas (CAPSTONE): a multi-center, single-arm, phase 2 trial

Article References: Jiang, J., Wei, Y., Yang, B., Liu, X., Cang, S., Song, Q., Wang, H., Jin, Z., Wang, J., Ye, F., She, F., Kou, H., Zhu, B., & Chu, Q. (2026). Camrelizumab plus famitinib as first-line treatment for locally advanced or metastatic pulmonary sarcomatoid carcinomas (CAPSTONE): a multi-center, single-arm, phase 2 trial. eClinicalMedicine, 101, Article 104285. https://doi.org/10.1016/j.eclinm.2026.104285

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104285

Keywords: pulmonary sarcomatoid carcinoma, camrelizumab, famitinib, immunotherapy, antiangiogenic therapy, phase 2 trial, non-small cell lung cancer, PD-1 inhibitor, progression-free survival, tumor mutational burden, single-cell RNA sequencing, CAPSTONE trial