Efficacy at a cost: camrelizumab and famitinib within the expanding landscape of combination therapies

Cervical cancer remains the second most common malignancy among women worldwide. Despite being frequently diagnosed at potentially curative stages, it continues to impose a substantial global health burden and remains the second leading cause of cancer-related death among women globally (1). For patients with recurrent or metastatic disease, first-line therapy is based on a platinum-taxane backbone combined with bevacizumab, when not contraindicated, and immune checkpoint inhibitors (ICIs) such as pembrolizumab or atezolizumab (2-4). Although these strategies have significantly improved overall survival (OS), around one third of patients experience progression within the first 6 months, during the combination phase, highlighting an unmet need for effective second-line therapies.

The EMPOWER-Cervical 1 trial demonstrated that cemiplimab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, improved median OS [12 vs. 8.5 months; hazard ratio (HR) =0.69; 95% confidence interval (CI): 0.56–0.84] when compared with chemotherapy in the second-line setting (5). Antibody-drug conjugates (ADCs) have also emerged as a promising strategy. The phase III innovaTV 301 trial demonstrated improved outcomes with tisotumab vedotin, a tissue-factor-directed ADC linked to the microtubule-disrupting agent monomethyl auristatin E, compared with investigator’s-choice chemotherapy in patients as second- or third-line therapy (6). The trial showed a higher overall response rate (ORR) (17.8% vs. 5.2%), modestly improved progression-free survival (PFS) (4.2 vs. 2.9 months), with OS benefit (11.5 vs. 9.5 months; HR =0.70; 95% CI: 0.54–0.89). Regarding tolerability, grade ≥3 adverse events (AEs) were observed in 52% vs. 62.3% of patients, with anemia, urinary tract infection, and neutropenia being the most frequent in both groups. Discontinuation due to toxicity occurred in 14.8% of patients receiving tisotumab vedotin. AEs of special interest included ocular toxicity, peripheral neuropathy, and bleeding events, reported in 52.8%, 38.4%, and 42% of patients, respectively, although severe grade ≥3 toxicities of special interest were rare (6). Additional ADCs are being assessed in clinical trials. Anti-TROP-2 ADCs such as sacituzumab govitecan and sacituzumab tirumotecan have shown promising results in phase II trials, with ORR of 43% and 28%, respectively (7,8). Other promising ADC targets include mesothelin (particularly for non-squamous carcinoma), Nectin-4, and human epidermal growth factor receptor 2 (HER2). By contrast, single-agent chemotherapies achieve poor outcomes, with response rates of 5–10% and median PFS <3 months (4,5). In this setting, prioritizing symptom control and quality of life (QoL) is essential, and early integration of palliative care is key.

In a recent publication, Xia and colleagues reported the results of a randomized phase II trial comparing camrelizumab (anti-PD-1 antibody) plus famitinib [multitargeted receptor tyrosine kinase inhibitor (TKI) that blocks vascular endothelial growth factor receptor (VEGFR)2/3 and members of the TAM family] vs. camrelizumab monotherapy as second-line treatment for ICI-naïve recurrent or metastatic cervical cancer (9). The primary endpoint was ORR, while PFS was a secondary endpoint. An additional investigator’s-choice chemotherapy arm was initially included but discontinued following an amendment prompted by the EMPOWER-Cervical 1 interim analysis. Randomization was stratified by histologic subtype and programmed death-ligand 1 (PD-L1) expression.

The study by Xia and colleagues met its primary endpoint, demonstrating an improvement in ORR with camrelizumab plus famitinib compared with camrelizumab alone (42.9% vs. 22.2%) (9). Median PFS was 7.2 months with the combination vs. 4.0 months with monotherapy (HR =0.54; 95% CI: 0.36–0.83). With a median follow-up of 14.1 months, the combination also showed a trend towards improved OS (20.2 vs. 14.9 months), although data remain immature. The performance of camrelizumab monotherapy was comparable to that observed for cemiplimab in the EMPOWER-Cervical 1 trial (5). In terms of safety, grade ≥3 treatment-related AEs occurred in 84.8% vs. 60% of patients in the combination vs. monotherapy arms, most commonly neutropenia (23.9% vs. 1.9%), hypertension (22.9% vs. 0%), and anemia (20% vs. 1.9%). Other noteworthy toxicities included diarrhea [35.3% (3.8% grade ≥3) vs. 3.8% (0% grade ≥3)], palmar-plantar erythrodysesthesia [28.6% (7.6% grade ≥3) vs. 0%], and weight loss (21.9% vs. 5.7%). Treatment discontinuation due to toxicity occurred in 16.2% vs. 3.8% of patients. Importantly, no cases of fistula formation or vaginal bleeding were reported—AEs that have limited the use of other TKIs in cervical cancer. No patient-reported outcome (PRO) data are available, limiting interpretation of the regimen’s tolerability.

Antiangiogenic therapy has a strong biological rationale in cervical cancer, as angiogenesis is a well-recognized hallmark of tumor progression in cervical cancer. Bevacizumab, an anti-VEGF monoclonal antibody, has long been incorporated into first-line therapy, improving OS outcomes (10). In contrast, early-phase trials of other antiangiogenic TKIs have reported modest single-agent activity, with ORR ranging from 0 to 9% (11,12). The combination of TKIs and immunotherapy has shown synergy in treatment-refractory malignancies such as renal cell carcinoma and endometrial cancer, supported by a solid biological rationale: TKIs modulate the tumor microenvironment, normalize tumor vessels, reduce hypoxia, and enhance immune infiltration (13), whereas ICIs reinvigorate exhausted T cells (Figure 1). Indeed, other early-phase trials combining antiangiogenic TKIs and anti-PD-1/PD-L1 inhibitors in cervical cancer have shown encouraging and consistent ORR and PFS results, similar to those reported by Xia and colleagues (14,15).

Figure 1 Novel ICI combination strategies in recurrent or metastatic cervical cancer. ADC, antibody-drug conjugate; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HER2, human epidermal growth factor receptor 2; ICI, immune checkpoint inhibitor; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TAA, tumor-associated antigen; TKI, tyrosine kinase inhibitor.

The phase II trial by Xia et al. was open-label and randomized, stratified by histologic subtype and PD-L1 expression (9). Nevertheless, some imbalances were observed across prognostic subgroups. Notably, prior bevacizumab exposure differed between arms (27.6% vs. 42.6%). As there is limited experience using antiangiogenic TKIs after bevacizumab, exploration of subgroup analyses assessing efficacy and toxicity in bevacizumab-exposed patients would be informative.

While ORR and PFS are useful indicators of activity, OS and QoL remain the most clinically meaningful endpoints in this setting (16,17). Future phase III studies should prioritize these outcomes, as they ultimately determine the real-world value of novel regimens in a population with limited life expectancy, in whom symptom control is paramount. When combining ICI and TKIs, toxicity management and mitigation strategies are essential. In the camrelizumab plus famitinib combination, toxicities such as palmar-plantar erythrodysesthesia, weight loss, and diarrhea may significantly impact tolerability and QoL, as reflected in the substantial discontinuation rate (16.2%)—a finding that warrants caution (9).

Although camrelizumab plus famitinib demonstrated promising activity, with ORR and PFS exceeding those of available second-line treatments (5,6,9), its applicability to current clinical practice is limited. ICIs are now part of first-line standard of care following the KEYNOTE-826 and BEATcc trials (2-4). Therefore, most real-world patients will have received prior ICI—a population not represented in this trial.

The combination has additionally been explored in the first-line setting. Wu and colleagues presented results from a randomized phase III trial at the European Society for Medical Oncology (ESMO) 2025 comparing camrelizumab plus famitinib with platinum-based chemotherapy with or without bevacizumab in advanced squamous cervical cancer (18). The study demonstrated improved PFS (11.1 vs. 7.5 months; HR =0.68; 95% CI: 0.53–0.86) and OS (34.4 vs. 23.4 months; HR =0.65; 95% CI: 0.49–0.86), while ORR was similar between arms. However, interpretation is limited by a suboptimal control arm lacking ICIs and only 30% of patients receiving bevacizumab. Thus, the control arm underperformed compared with pivotal first-line trials. Toxicity was again a concern: 87.3% of patients receiving camrelizumab plus famitinib experienced grade ≥3 AEs vs. 67.1% in the control arm (18). Frequent AEs included neutropenia [75% (29.1% grade ≥3) vs. 70% (51.2% grade ≥3)], anemia [70% (18.2% grade ≥3) vs. 75.6% (19.7% grade ≥3)], proteinuria (52.3% vs. 18.3%), hypertension (49.5% vs. 3.8%), diarrhea (41.8% vs. 3.8%), and palmar-plantar erythrodysesthesia (35% vs. 9.5%). Dose reductions were required in 65% of patients in the combination arm compared with 12.2% in the chemotherapy arm, and treatment discontinuations occurred in 13.6% vs. 6.6%, respectively. No PRO data were reported. Whether this combination could eventually replace standard chemotherapy with bevacizumab and ICI regimens would require further evaluation in randomized trials with contemporary comparators.

Beyond this, other combination strategies have shown promise in cervical cancer (Figure 1), particularly ADC plus ICI regimens. In the innovaTV 205 trial, the cohort receiving tisotumab vedotin plus pembrolizumab (n=34) demonstrated an ORR of 35.3% in the second-line setting (19). In a phase II study evaluating sacituzumab tirumotecan—a TROP-2-directed ADC linked to an anti-topoisomerase I payload—combined with pembrolizumab, the 38-patient cervical cancer cohort achieved an ORR of 57.9%, with 68.8% of patients previously treated with anti-PD-1/PD-L1 therapy (20). Grade ≥3 AEs occurred in 47.4% of patients, mainly neutropenia (23.7%), anemia (21.1%), and leukopenia (15.8%), with low treatment discontinuations (2.6%).

Other strategies, including combinations of ICIs (Figure 1), are also under evaluation—most notably anti-PD(L)-1 plus anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) regimens. In the first-line setting, the phase III Compassion-16 trial randomized patients to receive cadonilimab—a bispecific PD-1/CTLA-4 antibody—vs. placebo, each in combination with platinum-based chemotherapy with or without bevacizumab (21). Cadonilimab improved median PFS (12.7 vs. 8.1 months; HR =0.62; 95% CI: 0.49–0.80) and OS (not reached vs. 22.8 months; HR =0.64; 95% CI: 0.48–0.86). Immune-related AEs occurred in 46% of patients, including grade ≥3 events in 10%, a comparable rate to KEYNOTE-826 (3). However, in the absence of an anti-PD-1 agent in the control arm, the true incremental benefit attributable to CTLA-4 blockade cannot be reliably determined. In later lines, CheckMate 358 reported ORRs of 26–40% with nivolumab plus ipilimumab (22), while balstilimab plus zalifrelimab achieved an ORR of 25.6% in ICI-naïve disease (23).

In conclusion, the randomized phase II trial by Xia et al. demonstrated the significant efficacy of a TKI-ICI combination in metastatic recurrent cervical cancer after platinum therapy. However, in an era where most patients will have received prior ICI in the first-line setting, and treatment decisions are increasingly guided by tolerability and PROs, the clinical space for camrelizumab plus famitinib appears narrow. Unless future studies demonstrate meaningful benefit in immunotherapy-pretreated populations, this combination is likely to remain a proof of concept rather than a practice-changing option. Emerging ADC-ICI combinations show encouraging efficacy, and as these therapies move into earlier lines, it will be essential to determine their impact in PROs to balance activity with safety.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-73/coif). A.M. reports research funding (ASCO Conquer Cancer, ISCIII, SEOM, GEICO, AECC); honoraria for lectures (AZ, AbbVie, GSK, MSD, Eisai, Pharma&); travel support (AZ, GSK, MSD); and advisory board participation (AZ, AbbVie, Daiichi Sankyo, Genmab, Lilly, MSD, Eisai, Pharma&). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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