Authors: Rayan Kabirian, Mathilde de Saint Ghislain, Olivia Le Saux, Laurent Mathiot, Jean-Sébastien Frenel, Paule Augereau, Alexandra Forestier, Jean David Fumet, Lauriane Eberst, Stanislas Quesada, Elsa Kalbacher, Céline Lescure, Thibault De La Motte Rouge, Juan Francisco Grau Bejar, Solenn Barraud, Thomas Genevee, Diana Bello Roufai, Manuel Rodrigues, and Alexandra Leary.
Why Is ICI Rechallenge an Important Question?
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of both cervical and endometrial cancers. Agents targeting the PD-1/PD-L1 pathway—including pembrolizumab, dostarlimab, durvalumab, cemiplimab, and atezolizumab—have become standard therapies in selected patients, particularly those with PD-L1-positive cervical cancer or mismatch repair-deficient (MMRd) endometrial cancer.
Despite these advances, an important clinical question remains unanswered:
Can immunotherapy work again after a patient has previously received and discontinued an immune checkpoint inhibitor?
This strategy, known as ICI rechallenge, has generated increasing interest across oncology. Rechallenge may be considered after treatment discontinuation due to immune-related toxicity, completion of a fixed course of therapy, or disease progression following an initial response. While encouraging data have emerged in melanoma, renal cell carcinoma, and non-small cell lung cancer, evidence in gynecologic cancers has been extremely limited.
To address this gap, investigators from ten French academic centers conducted the RICE Study, the largest multicenter analysis evaluating immune checkpoint inhibitor rechallenge in recurrent or metastatic cervical and endometrial cancers.
Study Design
The RICE study was a national, multicenter, retrospective observational study conducted across ten French academic institutions.
Investigators reviewed medical records of patients treated between November 2015 and June 2025.
Eligible patients had:
- recurrent or metastatic cervical or endometrial cancer,
- prior treatment with an immune checkpoint inhibitor,
- subsequent retreatment with another course of PD-1 or PD-L1 blockade.
Rechallenge consisted primarily of anti-PD-1 therapy administered either alone or in combination with chemotherapy or targeted therapy.
Patient Population
A total of 39 patients underwent immune checkpoint inhibitor rechallenge.
The cohort included:
- 20 patients (51%) with cervical cancer
- 19 patients (49%) with endometrial cancer
Among patients with endometrial cancer:
- 68% had mismatch repair-deficient (MMRd) tumors, a population known to derive substantial benefit from PD-1 blockade.
The mean age at diagnosis of metastatic disease was 56.9 years, and most patients presented with recurrent rather than de novo metastatic disease.
Treatment Characteristics
Most patients initially received PD-1 inhibitors during first immunotherapy (ICI1).
At rechallenge (ICI2):
- 92% received anti-PD-1 therapy
- 72% received immunotherapy without concurrent chemotherapy
Patients underwent a median of two separate immune checkpoint inhibitor treatment courses, although some received up to four different ICI regimens throughout their disease course.
Primary Endpoint: Objective Response Rate
The primary objective of the RICE study was to compare the efficacy of the initial course of immune checkpoint inhibitor therapy (ICI1) with immune checkpoint inhibitor rechallenge (ICI2). To evaluate true rechallenge after disease progression, investigators excluded 10 patients who restarted immunotherapy following toxicity without intervening progression, leaving 29 patients for the efficacy analysis.
- Objective response rate (ORR) during initial immunotherapy (ICI1): 76% (22/29 patients)
- Objective response rate (ORR) during ICI rechallenge (ICI2): 52% (15/29 patients)
- More than half of the patients achieved an objective response despite prior exposure to immunotherapy.
- Among the 8 patients who achieved a complete response during initial immunotherapy, 5 (62.5%) maintained a complete response after rechallenge.
Progression-Free Survival
Although progression-free survival was shorter after rechallenge, patients continued to derive meaningful clinical benefit.
- Median progression-free survival with initial immunotherapy (ICI1): 11.0 months (95% CI, 8.7–19.0)
- Median progression-free survival after ICI rechallenge (ICI2): 6.0 months (95% CI, 4.0–16.0)
- Disease control remained clinically meaningful despite a shorter duration of response during the second course of immunotherapy.
Safety
Safety was another important objective of the study.
Among patients who discontinued their first immunotherapy because of immune-related adverse events, the most common toxicities were:
- Colitis (32%)
- Hepatotoxicity (11%)
During immune checkpoint inhibitor rechallenge:
- Only 13% of patients discontinued treatment because of toxicity
Overall, the investigators concluded that retreatment was associated with a manageable safety profile, with relatively few patients requiring permanent discontinuation because of recurrent immune-related adverse events.
Why Might Immunotherapy Work Again?
The biological rationale for immune checkpoint inhibitor rechallenge is increasingly supported by preclinical and clinical evidence.
Several mechanisms may restore sensitivity to PD-1 blockade after an initial course of treatment:
- chemotherapy may increase tumor antigen release and stimulate immune recognition;
- radiotherapy can induce immunogenic cell death and remodel the tumor microenvironment;
- targeted therapies may alter immune signaling and reduce immunosuppressive pathways;
- treatment-free intervals may allow recovery of exhausted T cells and partial restoration of immune function.
In highly immunogenic tumors such as HPV-associated cervical cancer and MMR-deficient endometrial cancer, these mechanisms may create an opportunity for renewed antitumor immune responses during rechallenge.
Clinical Implications
Although immune checkpoint inhibitor rechallenge is not currently considered a standard treatment strategy, the RICE study provides important evidence supporting its feasibility in selected patients.
The observed 52% objective response rate, together with a median progression-free survival of 6 months and an acceptable toxicity profile, suggests that rechallenge may represent a reasonable option for carefully selected patients when other effective therapies are limited.
Importantly, these results should be interpreted cautiously. The study was retrospective, included only 29 evaluable patients for efficacy, and treatment approaches were heterogeneous across participating centers. Prospective clinical trials will be necessary to identify the patients most likely to benefit and to determine the optimal timing and sequencing of immune checkpoint inhibitor rechallenge.
The Bottom Line
The RICE Study is the largest multicenter analysis to date evaluating immune checkpoint inhibitor rechallenge in recurrent or metastatic cervical and endometrial cancers. While responses were lower than during the initial course of immunotherapy, more than half of evaluable patients responded to retreatment, progression-free survival remained clinically meaningful, and toxicity was generally manageable.
These findings suggest that immune checkpoint inhibitor rechallenge may become an important strategy for selected patients with gynecologic cancers. Future prospective studies incorporating predictive biomarkers and optimized treatment sequencing will be essential to define its role in routine clinical practice.
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Gynecological Cancers, Cancer Vaccines & Immunotherapy: Are We Near Elimination?