Combination multikinase inhibition and checkpoint blockade in RAIR DTC

Antiangiogenic multikinase inhibitors (MKIs) targeting vascular endothelial growth factor receptor (VEGFR) are standard systemic therapy for patients with radioactive iodine refractory (RAIR) differentiated thyroid cancer (DTC). Specifically, sorafenib and lenvatinib are approved in the frontline setting, whereas cabozantinib is approved in the second line. While all of these agents were approved based on large randomized phase III trials (1-3), the control arm in all three of these trials was placebo. Response rates, durability of response, and tolerability of these MKIs are suboptimal, especially when compared to selective NTRK- and RET-targeted agents which are also available, and preferentially used, for patients whose tumors harbor a corresponding sensitizing alteration (4). The optimal sequencing of agents including MKIs and targeted therapies, particularly in DTCs harboring genomically actionable alterations such as BRAF V600Em , is not fully established, and is being studied in a cooperative group trial (5).

In the second line setting after progression on prior MKI, the COSMIC-311 trial established superior response and progression-free survival (PFS) of cabozantinib compared to placebo (3,6). In this study, patients on the cabozantinib arm had an overall response rate (ORR) of 11%, and a PFS of 11 months—both indisputably better than the placebo control arm, but markedly less impressive than the 40% ORR reported in an earlier single-arm phase II study of cabozantinib (7) (Table 1). There were some important differences between the phase II and phase III cabozantinib DTC trials, including in the eligible population (all histologic subtypes allowed in phase II versus only papillary and follicular subtypes allowed in phase III), prior treatment exposure to lenvatinib (4% in phase II versus 73% on phase III), and dosing regimen (dose escalation to 80 mg daily dose allowed in phase II trial, and noted in 16% of patients). Conventional chemotherapy agents, including doxorubicin and platinum-based approaches, have historically shown limited efficacy with response rates and substantial toxicity (13), although platinum with pemetrexed has been recently reported in a case series to produce some durable responses in salvage settings (14).

Given this landscape of limited effective and well-tolerated treatment options for RAIR DTC, especially in patients without targetable tumor genomic alterations (e.g., BRAF, NTRK, RET), there is a clear unmet need to investigate novel therapies, and several such trials have been conducted in the last 5 years (Table 1). Immune checkpoint inhibitors (ICIs), particularly programmed death (PD)-1 blockade which have revolutionized the treatment paradigm of multiple solid cancers, have thus far produced disappointing results in RAIR DTC. Pembrolizumab monotherapy was associated with a response rate of only 6.8% in the DTC cohort of the phase 2 KEYNOTE-158 study, and only 8.7% even in the PD ligand-1 (PD-L1) positive subgroup (11). Multiple factors, including low tumor mutational load and a relatively immunologically cold tumor microenvironment, are thought to contribute to the low responsiveness of DTC to PD(L)-1 inhibition. Notably, more aggressive forms of thyroid cancer including poorly differentiated thyroid cancer (PDTC)/differentiated high grade thyroid cancer (DHGTC) and anaplastic thyroid cancer (ATC) seem to exhibit higher responsiveness to checkpoint inhibitors (8).

Several approaches have been studied to overcome this immune non-responsiveness and enhance responses to immunotherapy. The first is combination of PD(L)-1 inhibition with VEGF-targeted therapy. The rationale for this approach is based on the fact that VEGF activity mediates immune suppression and evasion in the tumor microenvironment, and thus targeting VEGF may normalize abnormal tumor vasculature, increase infiltration of immune effector cells, and enhance responsiveness to ICI (15). A combination of pembrolizumab and lenvatinib has shown promising efficacy in ATC/PDTC (16), with response rate of 52%, and is now listed in the National Comprehensive Cancer Network (NCCN) guidelines. Pembrolizumab with lenvatinib was also studied in advanced RAIR DTC, in patients with either MKI-naïve (cohort 1, n=30) or lenvatinib-progressed (cohort 2, n=27) disease (12). While the response rate in MKI-naïve patients with the combination approach (ORR 68%) was similar to lenvatinib monotherapy, the median PFS of 26.8 months was longer than the 18.3 months observed with lenvatinib alone in the SELECT trial, with the important caveat of a cross-trial comparison (2). Additionally, 16% of patients in the lenvatinib-progressed cohort did experience a partial response (PR), with median PFS of 10 months. Thus, pembrolizumab added to lenvatinib in RAIR DTC is a promising strategy that warrants further investigation in the frontline setting, as well as a salvage approach after disease progression on lenvatinib.

Another rational approach to enhancing anti-PD(L)-1 efficacy, which has been successful in some solid tumors including melanoma and lung cancer but not in others such as head and neck squamous cell cancer, is to add cytotoxic T lymphocyte antigen (CTLA)-4 inhibition. Driven by observations of robust immune activation in pre-clinical patient-derived thyroid cancer models treated with dual PD-1 and CTLA-4 inhibition, a phase 2 clinical trial investigated combination of nivolumab and ipilimumab in 32 patients with RAIR DTC. This trial, however, did not meet its pre-specified endpoint in RAIR DTC, and reported ORR (all PR) of 9.4%, in line with responses rates previously seen with anti-PD-1 monotherapy in the KEYNOTE-158 (8). Notably, all responses were observed only in either oncocytic carcinoma or PDTC in this trial. In an updated analysis, the median duration of response was 30 months, while median PFS was 4.9 months (9). Durvalumab with tremelimumab, another PD-1/CTLA-4 combination, similarly, showed only modest activity with median PFS of 5.3 months and ORR of 8.1% (10).

In the current report, Konda et al. report results of a phase II investigator-initiated study that combined the above combinatorial approaches: a VEGF MKI (cabozantinib) with both PD-1 inhibitor (nivolumab) and CTLA-4 inhibitor (ipilimumab) (CaboNivoIpi) (17). The population for this study consisted of patients with RAIR DTC with disease progression on 1 prior line of VEGF targeted therapy. Unfortunately, the trial did not meet its prespecified endpoint for ORR within the first 6 months (target ≥70%, compared to null hypothesis of ≤40%) at a prespecified interim analysis, and thus closed after 11 patients were enrolled. Of note, this study design relied on data from the phase II cabozantinib trial and preceded the results of COSMIC-311, hence the ambitious selection of null hypothesis of ORR 40% and target ORR of 70%. At interim analysis, ORR within first six months was 10% (1/10 evaluable patients), while ORR at data cutoff was 20% (2/10). Additionally, median PFS (9 months) and overall survival (OS) (19.2 months) with CaboNivoIpi combination approach were similar to the results observed with cabozantinib monotherapy in the COSMIC-311 trial, within the limitations of cross-trial observations. Moreover, patients on this study experienced a high rate of treatment-related adverse events (TRAEs) (55% grade 3/4 TRAEs), primarily hypertension (attributable to cabozantinib) and immune-related AEs (IRAEs) including adrenal insufficiency, myocarditis, and hepatitis in 1 patient each. One patient also experienced a treatment-related myocardial infarction (MI) that led to death.

While this study did not meet its primary endpoint, it constitutes a valuable addition to the literature on systemic therapy in RAIR DTC, with several important lessons. First, the characteristics of the 11-patient cohort enrolled in this study are worth exploring, as several aspects may have contributed to the underperformance of this combination strategy. The histologic subtypes in this study were quite heterogeneous, with 5/11 oncocytic carcinoma and 2 each of papillary, follicular, and poorly differentiated. In comparison, COSMIC-311 enrolled only papillary and follicular thyroid cancers, which are known to have a better prognosis compared to other subtypes. Notably the most dramatic response (>70% shrinkage in sum of target lesions) was seen in a patient with follicular thyroid carcinoma, and the other PR was seen in a PDTC case, whereas no patients with oncocytic carcinoma had a confirmed PR. As the authors note in the discussion, oncocytic thyroid cancers, which were enriched in this study, have a distinct biology and may have lower responsiveness to VEGFR tyrosine kinase inhibitors (TKIs). Thus, the disappointing efficacy seen with CaboIpiNivo in this trial may have been due in part to an overrepresentation of a less-responsive histology (oncoyctic); future investigations may benefit from histology-specific approaches.

Another potential contributory factor to the modest response rate on this study was the prior treatment history of the cohort. While patients were only allowed to have 1 prior line of VEGFR-targeted therapy, the majority of patients (>70%) enrolled on this study had disease progression on lenvatinib, generally considered the more potent MKI, and the one patient who had prior sorafenib actually had received combination therapy with everolimus. The prior lenvatinib exposure is comparable to the 73% in phase III COSMIC-311 trial, but is in stark contrast to the 4% in the phase II trial. In addition, Tab. 1 of the accompanying article reports that 2 patients had also had prior dabrafenib plus trametinib (exclusion criteria in COSMIC-311), and 3 patients had received prior chemotherapy with or without radiotherapy (presumably in the definitive-intent setting). Moreover, a substantial proportion of patients had metastases in relatively uncommon sites, including peritoneum (n=2), brain (n=2), and other (n=4). Tab. 3 of the accompanying article also suggests a high rate of co-mutations in patient tumors including TERT alteration, HRAS/NRAS, and PIK3CA, as well as generally markers of low immune responsiveness [low tumor mutational burden (TMB), and PD-L1 expression; microsatellite stable (MSS), disease]. All of these features suggest a population with more heavily pretreated, predominantly lenvatinib-progressed, and aggressive disease biology, perhaps contributing to the disappointing efficacy results.

Beyond the response data, the safety experience on this trial provides additional sobering insights, and serves as an important reminder of the risks of combining potent therapies with significant toxicity profiles. The dosing regimen of anti-PD-1 and anti-CTLA-4 therapy on this study was nivolumab 240 mg q2weeks and ipilimumab 1 mg/kg q6weeks, for 4 cycles of six weeks, followed by nivolumab 480 mg q4weeks; this dosing regimen has been used in multiple studies and is thought to be more tolerable than higher doses of ipilimumab which were used in earlier melanoma studies. However, the IRAE risk of dual checkpoint inhibition remains substantial, and indeed on this trial, 1 patient experienced immune-mediated hepatitis while receiving cabozantinib/ipilimumab/nivolumab and subsequently myocarditis with cabozantinib/nivolumab alone. Another patient experienced grade 3 adrenal insufficiency. The grade 5 MI event may have been due to either cabozantinib or dual checkpoint inhibition. These serious IRAEs are known to be more common with CTLA-4 inhibition or combination therapy than with PD(L)1 blockade alone. In the nivolumab plus ipilimumab trial, any TRAEs and grade 3/4 TRAEs were reported in 81.6% and 32.7% patients, respectively; with no grade 5 adverse events (11). Finally, the CaboNivoIpi study reported development of secondary malignancies (lymphoma, lung cancer and pancreatic cancer) in 3/11 (27%) patients, which was thought to be unrelated, but warrants careful attention in future trials of these agents.

It is unclear whether cabozantinib precipitated or worsened these IRAEs, but the 40 mg starting dose evaluated in this study, albeit lower than that 60 mg starting dose evaluated in the phase II (allowing escalation to 80 mg dose) and phase III COSMIC-311 trials, was still associated with a 56% rate of dose reductions; related to its own side effects including hand-foot syndrome, diarrhea, mucositis, fatigue, and hypertension. Although MKI and checkpoint inhibitor toxicities are not generally thought to be synergistic or overlapping, this combination strategy, at least in this pretreated population, was challenging in terms of administration and tolerability.

Genotyping and biomarker results also deserve mention. Notably, the two patients who experienced PR had low or negative PD-L1, low-TMB (in one case), and MSS disease, while the one patient with PD-L1 expression of 100% disease achieved stable disease as best response (although with a 8.5-month duration of response). While these are small numbers, and it is not clear whether the PRs were a result of the cabozantinib or ipilimumab/nivolumab, these data do reinforce prior findings that these traditional markers of ICI responsiveness may not be particularly reliable in thyroid cancer. While the patient with follicular thyroid carcinoma had the deepest PR on the study, it was actually the patient with PDTC and PR who had the most durable response (27.3 months), further supporting the notion that combination checkpoint inhibition and MKI therapy may be most beneficial in poorly differentiated and ATC histologies (13).

In conclusion, CaboNivoIpi did not meet its efficacy endpoint in this study, likely due to a combination of histology, disease biology, pretreatment, and treatment efficacy factors; and was associated with both immune-mediated and VEGF-related adverse events, as well as secondary malignancies. However, the authors should be commended for successfully executing this clinical trial in a difficult to treat population. Data from this study contributes to the body of literature and understanding of therapeutic safety and efficacy in thyroid cancer. While CaboNivoIpi may not be the best path forward for all patients with pretreated RAIR DTC, specific subsets including follicular and PDTCs may be worthy of further study with this combination. In addition, future work should investigate novel MKIs with or without immunotherapy, particularly in biomarker- and histology-selected cohorts; redifferentiation approaches in both BRAFm and BRAF wild type DTC; combination treatments with improved tolerability; and optimal sequencing of these approaches in advanced thyroid cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Thyroid. The article has undergone external peer review.

Peer Review File: Available at https://aot.amegroups.com/article/view/10.21037/aot-2026-1-0006/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2026-1-0006/coif). L.S. reports grants or contracts from Pfizer, Merus, Immunocore, Frontier, ORIC, Tempus, Pyxis and Exelexis, and consulting fees from AstraZeneca, GSK, Merus/Genmab, Guardant, Flatiron, Eisai and Pyxis. K.S. reports grants or contracts from Merck and Pfizer, consulting fees from AmerisourceBergen, Guidepoint Global, Exelixis, Scholar Rock, Equinox Group, Pfizer, Dr Reddy’s Laboratories, Fore Biotherapeutics and Eisai, payment or honoraria from Pri-Med, Academy for Continued Healthcare Learning and BinayTara Foundation, and support for attending meetings and/or travel from Merck, Pfizer, Pri-Med and BinayTara Foundation. He’s a board member of Medscape. The authors have no other 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.

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