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Abstract

Background

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and combination regimens with targeted therapy are the current standard of care. Given their success in the first-line setting, re-use or continuation of ICIs in subsequent line settings has been a growing area of research interest.

Objective

This systematic review assesses the safety and efficacy of ICI re-challenge in patients with refractory mRCC.

Methods

Scopus, Embase, Cochrane, Ovid MEDLINE, and TRIP databases as well as clinicaltrials.gov were searched systematically for published prospective and upcoming clinical trials from inception to August 15, 2023. Inclusion criteria included patients with clear cell histology who had received at least one prior line of systemic therapy including an ICI. Trials with ICI as an intervention either in second-line or beyond were included and did not require a control arm. Safety and efficacy outcomes including overall response rates, overall survival, progression free survival, median duration of response, and grade 3 or higher adverse events (AEs) were extracted.

Results

Seven prospective studies and 49 upcoming clinical trials were identified. mPFS ranged from 3.7 to 12.2 months, with longer PFS rates being associated with ICI/VEGF combination re-challenge. However, data from the only phase III randomized controlled trial (CONTACT-03) did not support rechallenge of ICI with tyrosine kinase inhibitor (TKI) versus TKI alone. Rates of grade 3 or higher AEs ranged from 28–65%.

Conclusions

Given the paucity of current data regarding efficacy as well as high toxicity rates, patients with mRCC should not receive ICI-rechallenge unless as part of a prospective clinical trial.

Keywords

prospective studies carcinoma renal cell immune checkpoint inhibitors standard of care

Background

Metastatic renal cell carcinoma (mRCC) has long been recognized as an immune-regulated malignancy.^1,2 While this was first demonstrated by treatment with cytokines such as interferon-alfa and interleukin-2 (IL-2),³ treatment of mRCC has dramatically evolved due to the development of immune checkpoint inhibitors (ICIs) which block programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated-4 pathways.⁴

Seminal phase III randomized studies demonstrated that dual ICIs or ICIs in combination with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF TKIs) resulted in superior efficacy when compared to the VEGF TKI sunitinib alone in patients with treatment-naïve mRCC. These regimens include nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib.^5–12 Though these studies all demonstrated sustained clinical responses in patients treated with ICIs, extended long-term follow-up data have been reported for CheckMate-214, comparing nivolumab plus ipilimumab to sunitinib,¹³ and the KEYNOTE-426 study comparing pembrolizumab plus axitinib to sunitinib.¹⁴

With an extended median follow-up of 67.7 months, the CheckMate-214 study showed a maintained benefit of nivolumab plus ipilimumab compared to sunitinib in overall survival (OS) in the intention-to-treat (ITT) population.¹³ In addition, 63% of patients responding to treatment with nivolumab plus ipilimumab had an ongoing response at 5 years. Similar durable clinical benefit was reported in KEYNOTE-426.¹⁴ With extended median follow-up of 67.2 months, significantly superior OS was observed in ITT patients treated with pembrolizumab plus axitinib compared to sunitinib, and 43% of initially responding patients treated with pembrolizumab plus axitinib had an ongoing response at 5 years. These long-term responses have tantalized clinicians and investigators to rechallenge patients with mRCC with further ICI-based therapy, as evidenced by the rate of ICI rechallenge in CheckMate-214 (14% of patients treated with nivolumab plus ipilimumab) and KEYNOTE-426 (27% of patients treated with pembrolizumab plus axitinib).^13,14

There have been anecdotal reports of responses with ICI rechallenge in patients who had previously responded to ICIs but had discontinued therapy due to adverse effects. Furthermore, mechanistically a response with rechallenge even in those who developed progression on ICIs has some biological rationale. The development of new tumor antigens after initial treatment with an ICI could serve as new targets for the same ICI upon rechallenge. As well, long-term ICI treatment can lead to accumulation of immune-suppressive and regulatory T cells in the tumor microenvironment; thus ICI rechallenge could ‘reset’ the immunosuppressive environment and restore sensitivity to ICIs. Rechallenge could also activate different immune pathways, potentially overcoming the initial resistance mechanism, though this has not been thoroughly elucidated.¹⁵

Continuation or re-challenge of ICIs for refractory mRCC management has been evaluated retrospectively, with variable objective response rates (ORR) and duration of response (DOR).^16,17 Until recently, the clinical benefit associated with switching ICIs or rechallenge of ICIs in the treatment of mRCC was largely unknown yet real-world patterns suggests that more than 20% of patients in the United States undergo ICI rechallenge.¹⁸ This underscores the need for more rigorous clinical data in this area. As such, in this systematic review article, we summarize data from published and upcoming prospective clinical trials examining the efficacy of ICI re-challenge in the treatment of refractory mRCC.

Methods

Literature searches and eligibility criteria

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a search strategy developed with a reference librarian was utilized to search bibliographic databases (Scopus, Embase, Cochrane, Ovid MEDLINE, and TRIP) from inception to August 15^th, 2023 (Suppl 1). Searches were limited to studies published in English. One author (MP) conducted hand searches of clinicaltrials.gov from inception to December 15^th, 2023 to identify ongoing studies of immune checkpoint inhibitor rechallenge with RCC cohorts included.

Studies were included based on the PICOS (Population, Intervention, Comparison, Outcomes, Study Design) criteria as follows. The patient population for inclusion was mRCC patients with at least a cohort of clear cell histopathologic subtype and who had received at least one prior line of systemic therapy including an ICI. Trials which included ICI as an intervention either in second-line or beyond were included. Efficacy outcomes were required for inclusion in data extraction; Grade 3 or higher toxicity rates were extracted when available. While studies were required to be prospective for inclusion, a control arm was not required and was not an exclusion criteria. Unpublished trials were excluded from efficacy summary. We excluded all case reports, case series, cohort studies, retrospective studies, systematic reviews, and meta-analyses.

Data screening and extraction

Titles and abstracts were scanned for initial selection and two independent reviewers assessed for eligibility. Discrepancies were resolved by consensus, though a third reviewer was available to resolve disputes if they arose. A word document detailing the study information including the name of the first author, year of publication, category of the trial (phase I, II or III) and interventions received, was produced for eligibility screening. For each study, both reviewers extracted parameters of interest from published articles and supplementary materials including patient demographics, histologic subtypes, prior ICI treatment characteristics, interventions, follow-up period, and outcomes.

Results

The detailed flowchart of the selection process is depicted in Figure 1. The search strategy from the aforementioned databases initially identified 732 studies, 50 of which are not yet published but are either completed or continuing recruitment. After removal of duplicates, 647 published references were independently reviewed by two authors. Title and abstract screening yielded 11 articles subject to detailed review. Thirty citations were deliberated on to confirm they were ineligible for inclusion and ultimately 636 studies were excluded on the basis that they were review articles, retrospective studies, meta-analyses, case reports, case series, cohort studies, or references in which mRCC was not the subtype of cancer studied. After full-text article assessment, one study described as ambispective was excluded as there was no assigned intervention arm, one was excluded as it involved exclusively non-clear cell RCC, and two were excluded as no efficacy results were reported. After full review, 7 studies were retained for data extraction and their key findings are described below as well as in Table 1.

Figure 1.

Flow chart.

Table 1.

Characteristics of included studies.

Intervention strategy	Study name/reference	Study type	Sample size of pts undergoing ICI rechallenge (n)	Prior ICI	Intervention	ORR (95% CI) per RECIST criteria	Duration of response (95% CI)	mPFS/mOS (95% CI)	Rates of grade 3 or higher AEs
ICI monotherapy, sequential therapy, or dual combination	HRCN GU 16-260 cohort A: Atkins et al. (2022)	Response-adaptive phase II	n = 35	Nivolumab	Nivolumab and ipilimumab	11.5%	Not measured	Not measured	43%
ICI monotherapy, sequential therapy, or dual combination	FRACTION-RCC: Choueiri et al (2022)	Response- adaptive Phase II	n = 46	Anti-CTLA-4, anti-PD-1, or anti-PD-L1	Nivolumab and ipilimumab	17.4%	16.4 months (2.1 −27.0 months)	mPFS: 3.7 months (2.0–7.3 months) mOS: 23.8 months (13.2 months – not estimable)	28%
ICI and VEGF-TKI or other antiangiogenic combinations	KEYNOTE-146/ Study-111: Lee et al (2021)	Phase Ib/II	n = 104	Anti-PD-1 or anti-PD-L1	Pembrolizumab and lenvatinib	62.5%*	12.5 months (9.1–17.5 months)	mPFS: 12.2 months (9.5–17.7 months) mOS: not reached	64%
	IMmotion-150: Powles et al (2021)	Phase II	n = 44	Atezolizumab	Atezolizumab and bevacizumab	25%	18.3 months^# (95% CI, 11.6 months – not estimable)	mPFS: 11.1 months (5.1–17.0 months) mOS: Not measured	30%
	CONTACT-03^¶: Pal et al (2023)	Phase III	n = 262	Anti-PD-1 or anti-PD-L1	Atezolizumab and cabozantinib vs cabozantinib alone	41% (35–47%) vs 41% (35–47%) [per central review]	12.7 months (10.5–17.4) vs. 14.8 months (11.3–20.0)	mPFS: 10.6 (9.8– 12.3 months) vs 10.8 (10.0–12.5 months) mOS: 25.7 months (21.5 – NE) vs. NE (21.1 – NE)	55% vs. 47%
ICI and novel drug combinations	Parikh et al (2021)	Phase I/II	n = 28	Anti-CTLA-4, anti-PD-1, or anti-PD-L1	Nivolumab and ibrutinib	10.7% (3.7%—27.2%)	Not measured	mPFS: 2.5 months (1.9–4.8 months) mOS: 9.1 months (6.6–19.0 months)	65%
ICI and novel drug combinations	Silk et al (2022)	Phase Ib	n = 1	Anti-PD-1 and anti-PD-L1	Nivolumab and troriluzole	100%	>11 months	Not measured	N/A

*Per immune-related RECIST (irRECIST) criteria.

^#Estimated mDOR was reported in all patients who responded after advancing to second-line atezolizumab and bevacizumab, regardless of prior first line therapy (sunitinib or atezolizumab).

^¶Results reported as experimental group versus control.

NE = not evaluable.

Prospective studies examining ICI rechallenge

Dual ICI intensification

Dual ICI rechallenge has been studied in Phase II studies evaluating the sequential or combination use of nivolumab and ipilimumab. The multicenter phase II HCRN GU16–260 trial investigated a response-based approach to salvage dual nivolumab and ipilimumab in Cohort A of the study. In that cohort, 123 patients with treatment-naïve clear cell mRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 weeks of therapy (part A); subsequent nivolumab/ipilimumab was given to patients who developed PD before or stable disease (SD) at 48 weeks (part B). Of the 123 initially enrolled to the study, 35 patients were treated in part B. ORR was 11.4% by RECIST criteria and 17.1% per immune-related RECIST (irRECIST) criteria. Only one patient had a complete response. Grade 3 or higher AE rate was 43% in part B.¹⁹

The FRACTION-RCC study utilized an adaptive platform design to evaluate different combinations of ICI therapies. This open label, phase II trial enrolled patients into one of two tracks based on whether they were ICI naïve (Track 1) or not (Track 2). Patients in Track 2 had received anti-PD1, anti-PDL1, or anti-CTLA-4 treatment as a single agent, and were then randomized to receive nivolumab plus ipilimumab or other nivolumab-based combinations, and could cross over to receive a different combination if they developed progressive disease. Forty-six patients enrolled to Track 2 received ipilimumab and nivolumab; 50% had received 3 or more systemic lines of therapy. The ORR was 17%, all attributed as PRs (41% of patients with SD, 30% with PD, 11% not evaluable). Of 8 patients with PR, 5 had a greater than 50% reduction in tumor burden and 63% had an ongoing response. With a median follow-up of 38.8 months, median time to response was 2.9 months and median DOR was 16.4 months. mPFS was 3.7 months (95% CI, 2.0 to 7.3 months) and mOS was 23.8 months (95% CI, 13.2 months to not estimable). 28% of patients had grade 3 or 4 irAE and treatment discontinuation occurred in 8.7% of patients.²⁰

Data from HCRN GU16-260-cohort A and FRACTION-RCC do not appear to support a response-adaptive strategy consisting of PD-1/CTLA-4 inhibitors for the treatment of mRCC. More specifically, the addition of ipilimumab to nivolumab in a sequential manner results in incremental benefit when considered in the context of historical efficacy of nivolumab plus ipilimumab as observed in the CheckMate-214 trial.

ICI and VEGF-TKI and other antiangiogenic drug combinations

Given that the efficacy of front-line VEGF TKIs in combination with ICIs has been well-established in the treatment of mRCC,^8–12 its use in patients who have progressed on prior ICI therapy has also been of interest. Patients in the KEYNOTE-146/Study-111 open-label, single arm, Phase Ib/II study of lenvatinib plus pembrolizumab were stratified by treatment status- naïve, one prior line of therapy not including ICI, and ICI-pretreated. Of the 143 patients with ccRCC enrolled, 104 were ICI pre-treated. In the ICI-pretreated group, median age was 60 years old, with 64% of patients having received prior VEGF therapy, most commonly pazopanib (24%), and 92% having received ICI as their most recent line of therapy. The ORR by investigator assessment per irRECIST in this group was 62.5% (95% CI: 52.5–71.8%). This response rate varied by prior treatment regimen; patients who received nivolumab plus ipilimumab had an ORR of 61.5% while those patients who received an anti-VEGF with ICI or ICI with or without other treatment had ORRs of 38.9% and 57.4% respectively. The mDOR amongst all ICI pretreated patients was 12.5 months (95% CI: 9.1–17.5 months). mPFS was 12.2 months (95% CI: 9.5–17.7 months) while mOS was not reached in the median follow-up period of 16.6 months. Sixty four percent of patients in the ICI pretreated group experienced grade 3 or higher treatment related adverse events, the most common being hypertension (21%), proteinuria (10%), increased lipase (9%), and diarrhea (8%). 2 of the 104 (1.9%) patients experienced treatment-related deaths from gastrointestinal hemorrhage and an unclear etiology.²¹

The use of ICI plus a VEGF-directed monoclonal antibody (mAb) has also been examined. IMmotion 150 was a multicenter, open-label phase II study that randomized 305 patients with mRCC in a 1:1:1 manner to (1) atezolizumab plus bevacizumab, (2) atezolizumab alone, and (3) sunitib alone. Crossover to the atezolizumab plus bevacizumab group was allowed for patients on the other arms upon disease progression. Of 103 patients who progressed on atezolizumab monotherapy, 44 subsequently crossed over to treatment with atezolizumab plus bevacizumab. Though the study was not powered to examine solely those patients on prior atezolizumab monotherapy, the ORR was 25% (11/44; 95% CI, 13–40%) and the mPFS was 11.1 months (95% CI, 5.1–17.0 months) among these patients. Of nonresponders to first line atezolizumab, 23% had a response to combination therapy. Notably, safety was not analyzed by prior first line treatment, but of the 103 patients who initiated second-line atezolizumab and bevacizumab, 31 (30%) experienced a related grade 3/4 event and 12 (12%) had an adverse event that led to treatment discontinuation. The most common adverse events were rash, pruritus, and hypothyroidism.²²

The first phase III trial to address the question of PD-L1 challenge in patients with solid tumors and specifically with locally advanced or mRCC was CONTACT-03. This open-label, randomized controlled trial enrolled 522 patients to receive either atezolizumab and cabozantinib or cabozantinib alone after experiencing disease progression on prior ICI therapy. Seventy-seven percent of patients were male, the median age was 62 years old, 79% had histology consistent with dominant clear cell without sarcomatoid features, and 77% had IMDC intermediate or poor risk disease. Fifty-three percent had received ICI as first line therapy and 64% had been previously undergone treatment with VEGF-TKIs. After a median follow-up of 15.2 months, compared to cabozantinib monotherapy, there was no difference in mPFS (10.6 months vs 10.8 months), mOS (25.7 months vs not evaluable; stratified HR 0.94 [95% CI 0·70–1·27]; p = 0·69), or mDOR (12.7 vs 14.8 months) with atezolizumab plus cabozantinib. Adverse events of any grade or cause in the ICI plus TKI group included diarrhea (65%), palmar-plantar erythrodysethesia syndrome (39%), and decreased appetite (38%) with similar rates in the cabozantinib group. However, 48% of patients in the combination treatment arm had a serious adverse event and 16% discontinued treatment as a result while 33% patients in the monotherapy arm experienced serious adverse events and 4% discontinued treatment. With these results, CONTACT-03 established that the addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity.²³

Ultimately, KEYNOTE 146 and IMmotion-150 demonstrated varied ORRs but consistently high toxicity rates with the combination use of an ICI and antiangiogenic agent. Furthermore, the only available phase III data examining ICI rechallenge and specifically the combination of an ICI and a VEGF inhibitor does not support this therapeutic approach either.

ICI and novel drug combinations

Prospective studies have examined the safety and efficacy of ICI rechallenge in combination with therapies that may modulate the immune response and possibility potentiate the ICIs through varying mechanisms. Inhibition of Bruton's tyrosine kinase (BTK), which is highly expressed on myeloid derived suppressor cells, promotes T cell activation and proliferation, demonstrating potential for improving the effectiveness of ICIs.^24,25 On the basis of these data and other studies demonstrating preferential inhibition of the Th2 response in favor of Th1 response with BTK inhibition, the safety and efficacy of ibrutinib plus nivolumab in patients who had completed at least one line of prior systemic therapy was studied in a Phase I/II trial. In total, 31 patients were enrolled, 28 (90%) patients had received prior ICI, 84% had prior nephrectomy and 87% had clear cell histology. Of the 28 patients evaluable for response, ORR was 10.7% (95%CI: 3.7%–27.2%) and all responders had received prior ICI; one patient (3.6%) had a complete response (CR), two patients (7.1%) had a partial response (PR), and 11 patients (35.5%) had stable disease (SD). With median follow-up of 29.9 months, mPFS was 2.5 months (95%CI, 1.9 −4.8) while mOS was 9.1 months (95% CI, 6.6 −19.0). 65% of patients experienced some grade 3 or higher adverse event.²⁶ Ultimately, this low ORR and high toxicity rate deters from further study of this combination without more correlative analysis.

The glutamate signaling pathway has been implicated in tumor growth and angiogenesis. The metabotropic glutamate receptor family (mGluR) is expressed on normal neurons as well as cancer cells and when activated by glutamate results in the stimulation of the PKC, MAPK, and PI3 K/AKT pathways. Accordingly, there has been interest in the use of riluzole, an glutamatergic signaling-modulating drug, as a cancer therapy. As riluzole blocks the release of gluatamate cells, it also acts as a functional inhibitor of mGluR1, thereby downregulating MAPK and PI3 K/AKT.^27,28 Neoadjuvant use of riluzole in patients with melanoma has also led to an increase in CD45+ leukocytes at the tumor-stromal interface.²⁹ Based on this mechanistic rationale, a phase Ib study examined the hypothesis that glutamate signaling blockade with troriluzole (BHV-4157) would prime the tumor microenvironment to enhance response to nivolumab. Fourteen patients with advanced solid tumors, including 2 with mRCC, were enrolled and 11 of 14 patients (1 of 2 mRCC) had received prior ICI. Patients were treated in a dose escalating fashion with troriluzole monotherapy (maximum dose of 280 mg twice a day) for a 14-day lead in followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. The most common treatment related adverse events in more than 5 patients were transaminitis and increased lipase whereas dose-limiting toxicities included grade 3 anorexia, fatigue, and atrial fibrillation. No treatments were discontinued due to AEs. Disease control was observed in 43% of patients, including the patient with nivolumab-refractory mRCC, who experienced disease stabilization for more than 11 months.³⁰ However, it is challenging to determine the applicability of these results given the lack of more patients with mRCC treated. For that reason, additional studies investigating the combination use of nivolumab and troriluzole exclusively in patients with mRCC would be required to justify continued consideration of this therapeutic approach.

Upcoming trials

A total of 52 studies were identified in clinicaltrials.gov, with 3 completed with results. Table 2 summarizes the findings of these remaining 49 trials. The majority of these ongoing trials examine nivolumab or pembrolizumab-based regimens, in combinations with VEGF TKIs, monoclonal antibodies targeting T-cell markers, and interleukins/T-cell growth factors. While approximately half of these trials are continuing recruitment, the remaining are active studies from which data and potential publications are expected in the near future. One such example is the much awaited Ti-Nivo2 trial. In the antecedent Ti-Nivo phase I/II clinical trial, the combination of tivozanib, a potent, highly selective VEGFR TKI that inhibits all 3 VEGFRs (VEGFR-1, 2, and 3), and nivolumab resulted in an ORR 56% (95% CI, 36.5%—75.5%) and mPFS of 18.9 months (95% CI, 16.4 months – not reached). In the subgroup analysis of patients who received prior treatment, ORR was 62% and median PFS was not reached, but this did not distinguish whether prior treatment included an ICI.³¹ Ti-Nivo2, a phase III, open-label, multicenter randomized controlled trial evaluates tivozanib plus nivolumab versus tivozanib monotherapy in patients with mRCC who have progressed on one or two prior lines of therapy including an ICI. The primary endpoint is PFS assessed by blind independent radiological review and secondary endpoints include OS, ORR, DOR, and safety and tolerability.

Table 2.

Summary table of upcoming clinical trials.

Trial	Phase	Histologic subtype of interest (ccRCC vs nccRC)	Prior ICI treatments	Agents	Mechanism of action	Recruitment status (as of January 2024)
			NIVOLUMAB-BASED		Nivolmab: anti-PD-1
NCT06053658	II	nccRCC	One prior line of any ICI except nivolumab	Nivolumab + tivozanib	Tivozanib: VEGF inhibitor	Recruiting
NCT04987203 (TiNivo-2)	III	Component of clear cell features	One prior line of any ICI	Nivolumab + tivozanib vs tivozanib	Tivozanib: VEGF inhibitor	Active, not recruiting
NCT03172754	I/II	Predominant clear cell subtype	Prior nivolumab + ipilimumab	Nivolumab + axitinib	Axitinib: VEGF inhibitor	Recruiting
NCT03177239	II	nccRCC	Nivolumab (per study protocol)	Nivolumab → nivolumab + ipilimumab	Ipilimumab: anti-CTLA-4	Active, not recruiting
NCT05239533	II	Component of clear cell features or carbonic-anhydrase-IX positivity via IHC	Anti-PD-1 or anti-PD-L1	177-Lu-girentuximab + nivolumab	177-Lu-girentuximab: radiolabeled carbonic-anhydrase-IX monoclonal antibody (mAb)	Recruiting
NCT04904302	II	ccRCC or with clear cell component	Anti-PD-1 or anti-PD-L1	Nivolumab + sitravatinib	Sitravanitib: TKI targeting TYRO3, AXL, MERTK receptors	Active, not recruiting
NCT03991130	II	Any histology	Anti-PD-1	Nivolumab + high-dose IL-2	IL-2: T-cell growth factor (TCGF)	Recruiting
NCT06034860	I	Any histology	Anti-PD-1 or anti-PD-L1	MT-8421 +/- Nivolumab	MT-8481: Engineered toxin body targeting CTLA-4	Recruiting
NCT04349267	I/II	Any histology	Anti-PD-1 or anti-PD-L1	BMS-986315 +/- nivolumab or cetuximab	BMS-986315: Anti-NKG2A mAb Cetuximab: EGFR inhibitor	Recruiting
NCT03228667 (QUILT-3.055)	IIb	Any histology	Anti-PD-1 or anti-PD-L1	N803 + ICI* +/- PD-L1 t-haNK	N803: IL-15 superagonist (TCGF) PD-L1 t-haNK: high affinity CD16 chimeric antigen receptor (CAR)	Active, not recruiting
NCT02983045 (PIVOT-02)	I/II	Any histology	Prior ICI not mandatory but allowed	NKTR-214 +/- nivolumab	NKTR-214: CD122 agonist	Completed
			PEMBROLIZUMAB-BASED		Pembrolizumab: anti-PD-1
NCT04626518 (MK-3475-03B)	I/II	ccRCC	Anti-PD-1 or anti-PD-L1	(1) Pembrolizumab + quavonlimab, (2) pembrolizumab + favezelimab, (3) pembrolizumab + MK-4830, (4) pembrolizumab + belzutifan, (5) pembrolizumab + lenvatinib, (6) belzutifan + lenvatinib	Quavonlimab: CTLA-4 mAb Favezelimab: anti-LAG-3 mAb MK-4830: myeloid-specific ILT4 receptor mAb Belzutifan: hypoxia-inducible factor 2 alpha (HIF2α) inhibitor Lenvatinib: VEGF inhibitor	Active, not recruiting
NCT03149822	I/II	Any histology	Any prior ICI allowed except pembrolizumab	Pembrolizumab + cabozantinib	Cabozantinib: VEGF inhibitor	Active, not recruiting
NCT04374877	I/Ib	Any histology	Any prior ICI	SRF388 +/- pembrolizumab	SRF388: anti-IL-27 mAb	Recruiting
NCT05155033	II	ccRCC	Anti-PD-1 or anti-PD-L1	Aldesleukin + pembrolizumab	Aldesleukin: recombinant IL-2 (TCGF)	Recruiting
NCT05653882	I	Any histology	Prior ICI not mandatory but allowed	AB248 +/- pembrolizumab	AB248: CD8-targeted IL-2	Recruiting
NCT05585034	I	Any histology	Prior ICI not mandatory but allowed	XmAb808 + pembrolizumab	XmAb808: B7-H3 and CD28 bispecific antibody	Recruiting
NCT03474497 (UCDCC #272)	I/II	Any histology	Anti-PD-1 or anti-PD-L1	Intralesional IL-2, radiotherapy (RT), and pembrolizumab	IL-2: TCGF	Recruiting
NCT03809624	I	Any histology	Anti-PD-1, anti-PD-L1 or anti-CTLA-4 Prior anti-PD-L1 requires minimum wash-out period of 24 weeks	INBRX-105+/- pembrolizumab	INBRX-105: 4-1BB and PD-L1 bispecific antibody	Recruiting
NCT05329532 (ModiFY)	I	Any histology	Prior ICI not mandatory but allowed	Modi-1 vaccine +/- pembrolizumab or nivolumab	Modi-1 vaccine: induction and expansion of CD4+ T cells via vimentin and enolase	Recruiting
NCT06052852	I/II	ccRCC	Any prior ICI that is considered SOC	BDC-3042 + - pembrolizumab	BDC-3042: Dectin-2 agonistic antibody	Recruiting
NCT04198766	I/II	Any histology	Any prior ICI that is considered SOC	INBRX-106 +/- pembrolizumab	INBRX-106: hexavalent OX40 agonist	Recruiting
NCT05098132	Ia/Ib	Any histology	Prior ICI not mandatory but allowed	STK-012 +/- pembrolizumab	STK-012: partial IL-2 agonist	Recruiting
NCT05311618	I	Any histology	Any prior ICI that is considered SOC	NGM438 +/- pembrolizumab	NGM438: anti-LAIR-1 antagonist mAb	Recruiting
NCT04234113	I	Any histology	Any prior ICI that is considered SOC	SO-C101 +/- pembrolizumab	SO-C101: IL-15 receptor agonist	Active, not recruiting
NCT04977453	I	Any histology	Prior ICI not mandatory but allowed	GI-101 +/- pembrolizumab	GI-101: CD80 and IL-2 bispecific antibody	Recruiting
NCT05070247	I/II	Any histology	Anti-PD-1 or anti-PDL-1 with or without anti-CTLA-4	TAK-500 +/- pembrolizumab	Antibody drug conjugate (ADC) STING agonist	Recruiting
NCT04140526 (PRESERVE-001)	I/II	Any histology	Prior ICI not mandatory but allowed	ONC-392 +/- pembrolizumab	ONC-392: anti-CTLA-4 mAb	Recruiting
NCT04913337	I/II	Any histology	Any prior ICI that is considered SOC	NGM707 +/- pembrolizumab	NGM707: anti-ILT2/ILT4 mAb	Recruiting
NCT02298959	I	Any histology	Anti-PD-1 or anti-PD-L1	Pembrolizumab + ziv-aflibercept	Ziv-aflibercept: VEGF inhibitor	Active, not recruiting
NCT05479812	I	Any histology	Unclear (additional inclusion/exclusion criteria may apply)	WTX-124 +/- pembrolizumab	WTX-124: IL-2 prodrug	Recruiting
NCT05714553	I/II	Any histology	Prior ICI not mandatory but allowed	NUC-3373 +/- pembrolizumab	NUC-3373: targeted thymidylate synthase inhibitor	Recruiting
NCT04691375	I	ccRCC and nccRCC	Any prior ICI that is considered SOC	PY314 +/- pembrolizumab	PY314: TREM mAb	Active, not recruiting
NCT05215574	I	Any histology	Prior ICI not mandatory but allowed	NGM831 +/- pembrolizumab	NGM831: LILRB4 mAb	Recruiting
NCT04787042	I/II	Any histology	Prior ICI not mandatory but allowed	ST-067 +/- pembrolizumab	ST-067: IL18 agonist	Recruiting
NCT03239145	Ib	Any histology	Prior ICI not mandatory but allowed	AMG386 + pembrolizumab	AMG386: selective angiopoietin 1/2 – neutralizing peptibody	Active, not recruiting
NCT03454451	I	Any histology	Prior ICI not mandatory but allowed	CPI-006 +/- pembrolizumab, ciforadenant or pembrolizumab + ciforadenant)	CPI-006: CD73 mAb	Completed
NCT05269381 (PNeoVCA)	I	Any histology	Prior ICI not mandatory but allowed	Cyclophosphamide + peptide-based vaccine + pembrolizumab	Cyclophosphamide: alkylating agent Vaccine: personalized neoantigen targeting	Recruiting
NCT03589339	I	Any histology	Anti-PD-1	NBTXR3 activated by RT followed by monotherapy with pembrolizumab or nivolumab	NBTXR: functionalized hafnium oxide nanoparticles	Recruiting
NCT05128487	I/II	Any histology	Prior ICI not mandatory but allowed	NDI-101150 +/- pembrolizumab	NDI-101150: Hematopoietic progenitor kinase 1 inhibitor	Recruiting
NCT04902040	I/II	Any histology	Anti-PD-1, anti-PD-L1, or anti-CTLA-4	Plinabulin + RT + ICI* vs RT + ICI*	Plinabulin: microtubule destabilizing agent	Recruiting
NCT05708950 (VISTA-101)	I/II	Any histology	Prior ICI not mandatory but allowed	KVA12123 +/- pembrolizumab	KVA12123: V-region Ig-containing suppressor of T cell activation (VISTA) mAb	Recruiting
NCT02799095	I/II	Any histology	Prior ICI not mandatory but allowed	ALKS4230 +/- pembrolizumab	ALKS4230: engineered IL-2 fusion protein	Active, not recruiting
NCT04485013	I	Any histology	Unclear (additional inclusion/exclusion criteria may apply	TTX-080-001 +/- pembrolizumab	TTX-080-001: HLA-G mAb	Active, not recruiting
			DURVALUMAB-BASED		Durvalumab: anti-PD-L1
NCT03308396	Ib/II	Component of clear cell features	Anti-PD-1 or anti-PD-L1	Durvalumab + guadecitabine	Guadecitabine: DNA methyltransferase inhibitor	Active, not recruiting
NCT04504669	I	ccRCC	Prior ICI not mandatory but allowed	AZD8701 +/- durvalumab	AZD8701: antisense RNA inhibitor	Active, not recruiting
NCT03983954	I	Any histology	Anti-PD-1, anti-PD-L1, or anti-CTLA-4 for minimum 6 months	Naptumomab estafenatox + durvalumab	Naptumomab estafenatox: 5T4 targeting antigen-binding fragment (Fab) plus superantigen staphylococcal enterotoxin A	Active, not recruiting
			ATEZOLIZUMAB-BASED		Atezolizumab: anti-PD-L1
NCT03845166 (STELLAR-001)	I	Any histology (separate cohorts for ccRCC and nccRCC)	Prior ICI not mandatory but allowed	XL092 +/- atezolizumab or avelumab	XL092: VEGF, MET, TAM kinase inhibitor	Active, not recruiting
NCT03829501	I/II	Any histology	Anti-PD-1 or anti-PD-L1	KY1044 + atezolizumab	KY1044: anti-inducible T co-stimulator (ICOS) mAb	Active, not recruiting
			AVELUMAB-BASED (see QUILT-3.055 and STELLAR-001)		Avelumab: anti-PD-L1
			CEMIPLIMAB-BASED
NCT05864144	I/II	Any histology	Any prior ICI that is considered SOC	SNS-10 +/- cemiplimab	SNS-10: anti-VISTA mAb	Recruiting

*ICIs include: pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab.

Additionally, the search strategy implemented to identify published prospective studies identified 2 abstracts from Embase related to the ongoing PIVOT-02 trial, a phase I/II open-label study examining the safety and efficacy of NKTR-214, a CD122 biased agonist in combination with nivolumab (Table 2). NKTR-214 targets the IL-2 pathway to activating and expanding natural killer and effector CD8+ T regulatory cells within the tumor microenvironment, thereby improving tumor response to ICIs. The trial is enrolling patients with locally advanced or metastatic melanoma, NSCLC, RCC, urothelial carcinoma, or triple negative breast cancer. Patients who are ICI naïve and those who are relapsed/refractory to prior immunotherapy will be studied separately.^32,33

Discussion

While first-line treatment of mRCC incorporating ICI-based therapy is now an established approach, the safety and efficacy of immunotherapy rechallenge is currently unclear. This systematic review highlights not only the scarcity of randomized, prospective data in this area but also the significant toxicities associated with re-challenge of ICI. Amongst Phase I/II studies, albeit across a heterogenous patient population, mPFS ranged from 3.7 to 4.7 months for ICI re-challenge. While mPFS was longer with ICI/VEGF combination re-challenge (10.6 to 12.2 months), the contribution of ICI to efficacy is unknown in Phase I/II studies. Though tempting to favor the ICI/VEGF combinations as a rechallenge strategy, the rates of grade 3 or higher hypertension and proteinuria in particular pose a significant deterrent. Moreover, data from the only randomized, prospective Phase III study of re-challenge (CONTACT-03) do not support the use of atezolizumab with cabozantinib over cabozantinib alone. CONTACT-03 did further demonstrate increased toxicity with this combination approach as high rates of diarrhea (65%), palmar–plantar erythrodysesthesia syndrome (39%), hypothyroidism (36%), and hypertension (27%) were observed. Notably, this side effect profile is different from dual ICI regimens which are instead associated with high rates of immune-related adverse events, particularly colitis, asymptomatic pancreatitis, and dermatitis. As such, there is currently no evidence to support ICI-rechallenge, though the results of a key Phase III study (Ti-Nivo2) will further inform practice.

It is important to note that the ICI rechallenge studies that are outlined in this review are variable in terms of prior treatment. While prior ICI treatment was a requirement of consideration for this review, it was often not reported if patients had primary ICI-refractory disease or had progressed or relapsed after an initial response to ICI. Some patients received several lines of therapy prior to ICI-rechallenge. Thus, there may be heterogeneity of patients studied in these trials, and this may be worthwhile to consider in future trial design.

The strengths of this systematic review are the comprehensive search strategy undertaken, as well as our focus on published, prospective interventional trials of patients with ccRCC. The latter results in less confounding compared to the heterogeneity that may have resulted from including retrospective analyses. The greatest limitation of the review is the inherent paucity of large, prospective ICI-rechallenge trials with results. At the time our search strategy was implemented, results from the Phase II TITAN-RCC study had not yet been published, though were available in abstract form. This example of publication bias suggests that more data may be available in the near future which may further inform the role of ICI-rechallenge.

In addition to the late-stage Phase III Ti-Nivo2 study, it is striking that our search of active clinical trials revealed that ICI-rechallenge is still a vigorous area of clinical research in mRCC and other solid tumors. This may be a function of the challenges of drug development and clinical trial design but may also reflect that much is still unknown regarding ICI therapy. In particular, many ongoing trials examine the combination of approved ICIs with other immune modulating agents, such interleukin signaling inhibitors, and bispecific T cell engager antibodies, in the hopes that responses to rechallenge could require drug partners with distinct mechanisms of immune modulation.

In conclusion, this systematic review strongly supports that patients with mRCC should not receive ICI-rechallenge unless as part of a prospective clinical trial, given the lack of current data regarding efficacy and the potential harm to patients with ICI-rechallenge toxicity.

Supplemental Material

sj-docx-1-kca-10.1177_24684570241303351 - Supplemental material for The role of checkpoint inhibitor rechallenge in patients with metastatic renal cell carcinoma: A systematic review

Supplemental material, sj-docx-1-kca-10.1177_24684570241303351 for The role of checkpoint inhibitor rechallenge in patients with metastatic renal cell carcinoma: A systematic review by Kanishka Patel, Shuchi Gulati, Nicholas Mitsiades, Primo N Lara Jr and Mamta Parikh in Kidney Cancer

Footnotes

Acknowledgments

The authors acknowledge the assistance of Bruce Abbott, MLS, who assisted with executing the search strategy outlined here.

ORCID iD

Kanishka Patel

Author contributions

KP: conception, writing the article, analysis & interpretation of data; SG, NM: substantive review and revision; PNL: substantive review and revision, interpretation of data; and MP: conception, writing and revision, interpretation of data.

All authors had access to the data.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by NIH Cancer Center Support Grant 5P30CA093373-21.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Mamta Parikh, Shuchi Gulati, and Primo N Lara are editorial board members of this journal but were not involved in the peer-review process of this paper, nor had access to any information regarding its peer-review. Kanishka Patel and Nicholas Mitsiades have no conflicts of interest to report.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Supplemental material

Supplemental material for this article is available online.

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