Minimal Efficacy of Single-Agent Anti-PD(L)1 Rechallenge in Immunotherapy-Refractory Merkel Cell Carcinoma: A Retrospective Cohort Study of 16 Patients

1. Introduction

Merkel cell carcinoma (MCC) is an uncommon and aggressive skin cancer associated with exposure to extensive ultraviolet light, advanced age, and immunosuppression. The incidence of MCC is approximately 3,200 new cases per year in the United States and rising [1]. In the United States, around 80% of MCCs are induced by the Merkel cell polyomavirus (MCPyV), and the remaining 20% arise exclusively from mutations from ultraviolet radiation [2]. Approximately 40% of MCC patients experience disease recurrence and patients with advanced disease typically require systemic therapy [3].

Prior to 2017, cytotoxic chemotherapy was first-line treatment for advanced MCC. Though chemotherapy induces a response in about 60% of patients, durability is typically short-lived. Only ~5% of patients experience continued benefit from chemotherapy at 1-2 years [4].

In 2017, the first anti-programmed death-ligand-1 (anti-PD-L-1) immune checkpoint inhibitor (ICI), avelumab, was approved for use in the United States by the FDA, followed by the approvals of pembrolizumab (anti-PD-1 in 2018) and retifanlimab (anti-PD-1 in 2023). Anti-PD(L)1-ICI quickly overtook chemotherapy as the preferred first-line treatment for advanced MCC, with durable responses in ~50% of patients with MCC at 2 years. Since the introduction of ICI, there has been a >2-fold increase in survival at the population level for advanced MCC [5].

However, for the 50% who progress on first-line ICI, multidisciplinary input for salvage strategies is essential because there is no clear second-line option for treatment once ICI resistance develops. Salvage options often involve a combination ICI (e.g., addition of a CTLA-4 inhibitor) and radiation or surgery based on the disease progression pattern. However, enrollment in a clinical trial if feasible is often preferred in this setting. Trials for ICI-refractory MCC often test whether a novel agent can augment an anti-PD(L)1 agent (e.g., the MATRiX trial testing an ATR inhibitor ± avelumab; NCT05947500) [6].

Although presumed to have limited benefit, the efficacy of rechallenge with anti-PD(L)1 monotherapy has not been formally reported for patients with ICI-refractory MCC. In order to better contextualize outcomes from combination therapy trials in ICI-refractory disease, it is important to understand the potential benefit attributable to anti-PD(L)1-ICI alone in this setting. Thus, we assessed real-world outcomes of ICI-refractory patients within a Seattle-based MCC repository who received this salvage approach.

2. Materials and Methods

In brief, this is a retrospective analysis of a Seattle-based MCC observational repository with an eligibility cutoff of August 16, 2024. The repository was re-queried on May 13, 2025 to update available follow-up and outcomes. This repository was approved by the Institutional Review Board at Fred Hutch Cancer Center (IRB #6585, Seattle, WA, USA). Eligible patients were those who had progressed during or after first-line ICI and received salvage for MCC. Full original study criteria are available in the previously published study [7]. For the present study, the cohort consisted of a subset of patients who received anti-PD(L)1 monotherapy rechallenge. These patients progressed either while receiving first-line anti-PD(L)1 or within 12 weeks of their last dose.

Details of interventional treatments starting from initiation of first-line ICI to last follow-up date were captured. Characteristics of treatments, including start and end dates and objective responses with corresponding dates were extracted. Each eligible patient also had their electronic medical record manually reviewed for quality control and to construct the case descriptions included in this study.

2.1. Statistical Analysis

Time 0 for all analyses was defined as the initiation date of anti-PD(L)1 monotherapy rechallenge. Outcomes were progression free survival (PFS), disease-specific survival (DSS), and objective response rate (ORR). Progression-free survival (PFS) was defined as the duration from initiation of ICI rechallenge until next PD or death from any cause. Disease-specific survival (DSS) was defined as the duration from initiation of ICI rechallenge until death from MCC. Attribution of death to MCC was determined using clinical records from Seattle and collaborating medical teams based on the treating physician’s determination of the cause of death. Cause of death was classified as due to MCC, non-MCC, or unknown. In the case of unknown cause of death, DSS was censored at the time of death (n=3). Overall response rate (ORR) was defined as the fraction of patients that experienced an objective response (PR or CR) after initiation of ICI rechallenge before next PD or death divided by the total number of evaluable patients.

All statistical analyses were conducted using R version 4.5.0 (R Foundation for Statistical Computing, Vienna, Austria). PFS and DSS probabilities were estimated using the Kaplan-Meier estimator. Median PFS and DSS were estimated as the time corresponding to a 50% event-free probability on the Kaplan-Meier curve.

3. Results

At study initiation, there were 1848 MCC patients in the Seattle MCC registry, of which 334 patients received ICI for MCC (Figure 1) [7]. From these 334 patients, 106 underwent at least one salvage therapy after progressing on first-line anti-PD(L)1, thus meeting original study inclusion criteria [7].

Among these 106 patients, 16 had progressed within 12 weeks of their last dose of first-line ICI and received single-agent anti-PD(L)1 rechallenge during their salvage therapy course. This subset was not separately analyzed in the initial study [7].The median time to rechallenge after progression on first-line anti-PD(L)1 ICI was 51 days [IQR 22–92]).

A swimmer plot summarizing the number of systemic treatments received preceding rechallenge, and the anti-PD(L)1 rechallenge course of these patients is depicted in Figure 2. A corresponding per-patient summary is available in Table 1.

Median PFS was 2.2 months (95% CI: 1.3-5.4), and median DSS was 14.7 months (95% CI: 10.4-NR) (Figure 3). Median follow-up time from ICI rechallenge initiation was 12.5 months (IQR 5-21). Most patients switched between PD-1 and PD-L1 inhibitors (8 PD-L1 to PD-1; 3 PD-1 to PD-L1); 3 were rechallenged with the same agent and 2 switched to a different PD-1 inhibitor.

One of 16 patients in this study experienced an objective response (ORR 6%, 95% CI: 0.2-30%; partial response with same PD-1 inhibitor) to single-agent anti-PD(L)1 rechallenge, with progression 6 months thereafter. This case is described below.

3.1. Patient #1 (Responder)

A man in his 60s who presented with stage IV MCC involving the thyroid and left inguinal and pelvic lymph nodes experienced a complete radiographic response after 7 months of first-line pembrolizumab. His course was complicated by immune-related inflammatory arthritis, which was well controlled with prednisone 10 mg daily. At month 11, while still receiving pembrolizumab and low-dose prednisone, his disease recurred in the thyroid, pelvic lymph nodes, and newly perirenal region. Because this occurred during concurrent immunosuppression rather than with fully intact antitumor immunity, his ICI-refractory designation should be interpreted with caution. Pembrolizumab was discontinued at month 12 with the development of immune-related pancreatitis, managed with high-dose prednisone (100 mg daily, tapered) and mycophenolate mofetil (1 g twice daily).

Pembrolizumab was restarted at month 20 (261 days after discontinuation), defining time 0 for rechallenge; immunosuppression had been de-escalated to prednisone 7.5 mg daily beforehand. The patient experienced a partial response at 3 months of rechallenge (month 23), but the disease progressed approximately 10 months into rechallenge (month 30). Pembrolizumab was continued while local salvage was pursued, including radiation to bilateral renal metastases (25 Gy in 5 fractions). Recurrent immune-related arthritis of the same and new joints required low-dose prednisone, methotrexate, and tocilizumab. Pembrolizumab was discontinued after approximately 18 months of rechallenge (month 38) due to a combination of disease progression and treatment-related adverse events.

4. Discussion

For patients with ICI-refractory MCC, there remains a large unmet need for effective second-line therapies following progression on anti-PD(L)1 agents. Multiple ongoing clinical trials aim to address this gap; however, many incorporate continued anti-PD(L)1 therapy as part of the treatment backbone. In this setting, it is important to delineate the contribution of the prior ICI, on which the patient has already progressed, versus the added investigational therapy. Careful interpretation is required to ensure that any observed clinical benefit is attributable to the novel agent or combination strategy, rather than residual or confounding effects of continued ICI therapy. In this cohort, outcomes were dismal for patients who underwent a single-agent anti-PD(L)1 monotherapy rechallenge salvage strategy. Only 1 of 16 patients experienced a transient ~3-month partial response upon anti-PD(L)1 only rechallenge, suggesting that this monotherapy salvage strategy confers minimal benefit in the ICI-refractory setting. It also suggests that this approach is not an attractive or feasible trial arm for randomization in future MCC trial designs.

ICI rechallenge is a rational strategy for “late progressors” (when progression occurs >3 months after cessation of therapy), but the logic is weaker when disease progresses while drug is still present [7,8,9]. Anti-PD-1 antibodies can persist on T cells for over two months, so progression within this window more likely reflects true ICI-resistance rather than a late progression [10]. Since the literature defines ICI resistance inconsistently, and including late progressors may inflate apparent rechallenge response rates, we required documented progression within 12 weeks of the last dose of PD-1 pathway blockade for inclusion.

ICI rechallenge has been previously evaluated across multiple solid tumors, with overall modest efficacy outside of select clinical contexts. A systematic review including 3,579 patients reported a pooled ORR of 18.4%, with higher response rates observed among patients who previously benefited from ICI and those with longer initial treatment durations, suggesting that retained immune sensitivity is a key predictor of response [11]. Consistent with this, retrospective data in metastatic renal cell carcinoma (RCC) demonstrated an ORR of 23% with rechallenge, with responses enriched among prior responders but still observed in a minority of patients overall [12]. Importantly, these ICI rechallenge studies included cases where the ICI rechallenge mechanism were different (e.g., CTLA-4 instead of PD-1 inhibition). In MCC, the addition of a CTLA-4 inhibitor to anti-PD(L)1 therapy has been associated with an ORR of ~30% [13]. Therefore, we believe that these numbers would be even lower had it been limited to the same mechanistic class of ICI as in our study.

Prospective evidence further limits enthusiasm for routine anti-PD(L)1 rechallenge following progression. In the phase 3 CONTACT-03 trial, continuation of PD-(L)1 blockade with atezolizumab in combination with cabozantinib did not improve progression-free or overall survival and increased toxicity compared to cabozantinib monotherapy in patients with RCC [14]. In contrast, higher response rates have been reported in melanoma patients rechallenged after prior disease control rather than progression (ORR 55%) [15]. Collectively, these data indicate that anti-PD(L)1 ICI monotherapy rechallenge has limited benefit in ICI-refractory disease, supporting the need for alternative salvage approaches.

The sole responder in our cohort highlights the complexity of defining and managing ICI-refractory MCC in the setting of significant immune-related toxicity and concurrent immunosuppression. Although the patient technically met criteria for ICI-refractory disease at the time of progression, this occurred while receiving also systemic immunosuppressive therapy for immune-related adverse events, which may have attenuated antitumor immune activity. Rechallenge with pembrolizumab resulted in a meaningful but transient partial response for ~10 months, suggesting that some degree of immune sensitivity was retained despite prior progression. However, the eventual disease progression and repeated immune-related adverse events in this patient spotlights the limited durability of benefit with ICI rechallenge in this context. Consistent with broader experience in ICI-refractory MCC, effective disease control ultimately required a multimodal salvage approach incorporating continued immunotherapy alongside localized treatments such as radiation, reflecting the need for multidisciplinary salvage strategies in this challenging population. As noted in prior studies, a combination of radiation with ICI as salvage has been associated with survival benefit [7,16].

4.1. Limitations of Study

There are several limitations to this study. Given the study’s retrospective design of a single-center observational database, it is subject to selection bias. As a high-volume specialty referral care center for Merkel cell carcinoma with ready access to specialized care, patients may experience quicker turnaround and benefitted from readily available multidisciplinary input; generalizing results beyond this setting should be performed with caution. Such high-volume centers have been associated with improved survival outcomes in national database studies [17].

Furthermore, the small sample size of patients who underwent anti-PD(L)1 monotherapy rechallenge (n=16) limits statistical power. It also restricts the ability to perform subgroup analyses to identify clinical or treatment-related factors associated with response, such as prior duration of benefit from first-line ICI or immune-related toxicity history. Therefore, the findings may not fully capture the heterogeneity in outcomes across different patient subsets.

5. Conclusions

These findings suggest that anti-PD(L)1 monotherapy rechallenge after progression on first-line anti-PD(L)1 therapy provides minimal clinical benefit in patients with ICI-refractory MCC, with responses being rare and generally short-lived. In this cohort, most patients experienced rapid disease progression despite retreatment, reinforcing the limited utility of this strategy once resistance to initial ICI therapy has developed. After progression on first-line ICI, changing single-agents within the same mechanistic class is not an adequate salvage strategy.

These results have implications for clinical practice and trial design. In the salvage setting, emphasis should shift towards alternative multidisciplinary approaches, including combination immunotherapy (e.g., addition of anti-CTLA-4), novel agents (e.g., ATR inhibition), and multimodal strategies (e.g., addition of radiation to ICI). Additionally, future clinical trials in ICI-refractory MCC should likely avoid inclusion of an ICI monotherapy control arm, as the low likelihood of meaningful benefit may limit both patient and clinician enthusiasm for enrollment.