Novel combinations with programmed cell death 1 inhibitor for incurable recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC): is cabozantinib a front runner?

Immunotherapy with programmed cell death 1 (PD-1) inhibitors has led to change in the therapeutic landscape of recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC). Pembrolizumab is approved in the first line setting in programmed death-ligand 1 (PD-L1) positive [combined proportion score (CPS) score ≥1] HNSCC (1). Pembrolizumab with platinum and 5-fluorouracil (5-FU) is approved regardless of PD-L1 CPS score in RM HNSCC. Keynote 048 (1) compared pembrolizumab alone to platinum and 5-FU with cetuximab (EXTREME regimen) and compared pembrolizumab combination with platinum and 5-FU to platinum and 5-FU with cetuximab. The investigators reported a median progression-free survival (PFS) of 2.3 and 4.9 months, median overall survival (OS) of 11.6 and 13 months with pembrolizumab alone and pembrolizumab combined with chemotherapy respectively in HNSCC regardless of PD-L1 CPS score. The response rate (RR) with pembrolizumab alone was 17% and improved to 36% in combination with chemotherapy. Although pembrolizumab led to improvement in OS, modest responses rates and PFS underline the need for novel combinations in this setting. Biomarkers other than PD-L1 CPS score are also needed to tailor patient selection for novel combinations.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are known to be immunomodulatory and anti-angiogenic (2). Saba et al. (3,4) report the results of a phase 2 multicenter single arm trial combining cabozantinib with pembrolizumab in recurrent or metastatic HNSCC patients with no prior exposure to immunotherapy. In addition to standard inclusion and exclusion criteria about comorbidities, performance status and organ function, other exclusion criteria included: need for anticoagulation, cavitating lung lesions, invasion or encasement of major blood vessels or substantial bleeding history. Fifty patients were screened and 14 did not qualify due to these contraindications. A total of 36 patients were enrolled and 33 were evaluable for responses; 53% patients were never smokers; 80% of patients had known human papillomavirus (HPV) status with 47% being HPV/p16 positive; 61% of patients had an oropharyngeal primary; nasopharynx and paranasal sinuses primary were allowed and 16% of patients had a nasopharyngeal primary. PD-L1 CPS score was greater than or equal to 20 in half the patients. Although Epstein-Barr virus (EBV) status is not reported for patients with nasopharyngeal primary, it is fair to assume that about half to two thirds of the patients included in the trial are HPV mediated oropharyngeal cancers or EBV mediated nasopharyngeal cancers. Both these subgroups of HNSCC are known to have better prognosis and higher responses with immunotherapy (5).

The primary endpoint of the trial was overall response rate (ORR) which was met at 52%. Median OS was 22.3 months [95% confidence interval (CI): 11.7–32.9] with a 1-year OS of 68% (95% CI: 45.1–83.5%), median PFS was 14.6 months (95% CI: 8.2–19.6) and 1-year PFS was 54% (95% CI: 31.5–72%). In this update, they report the long-term outcomes of this combination. With a median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI: 18.8–56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% (95% CI: 38.9–76.8%). Fatigue (44.4%), diarrhea (33.3%) and hypothyroidism (33.3%) were the most common adverse events (AEs). Grade 3 or higher AEs were hypertension (11.1%), dysphagia (8.3%) and oral mucositis (5.6%). The authors report a dose reduction of cabozantinib in 44% patients and treatment discontinuation due to toxicities in 13.8% of patients. The authors concluded that the regimen was well tolerated. There were no new safety signals seen during the extended follow up. The investigators used multiplex immunohistochemistry (IHC) to correlate lymphoid and myeloid markers with clinical activity of the combination. Mesenchymal epithelial transition (MET) pathway exerts immunosuppressive effects in the tumor immune microenvironment (6). Consistent with cabozantinib’s known inhibitory action on MET, baseline tumor phosphorylated MET on IHC correlated with ORR (P=0.0055). Using multiplex IHC, the investigators found that higher baseline density of lymphoid markers CD8⁺ and CD103⁺ in the tumor core correlated with improved OS. Cabozantinib also exerts effect on tumor immune microenvironment by inhibiting polarization of macrophages to immunosuppressive M2 phenotype (7,8). Colony stimulating factor 1 receptor (CSF-1R) is a known regulator of tumor associated macrophages (9), a target of cabozantinib and high CSF-1R density in tumor core was associated with improved OS.

LEAP-010 (10) phase III randomized double-blind placebo-controlled trial investigated the combination of lenvatinib and pembrolizumab compared to placebo and pembrolizumab as first line therapy for recurrent or metastatic HSNCC with a CPS score ≥1. The primary end points were ORR, PFS and OS with duration of response and safety as key secondary endpoints. The trial accrued a total of 511 patients and reported a median PFS of 6.2 months (95% CI: 5.1–7.2) versus 2.8 months (95% CI: 2.0–4.0) (HR: 0.64, 95% CI: 0.50–0.81; P=0.0001), the corresponding ORR was 46.1% (95% CI: 38.6–53.7%) versus 25.4% (95% CI: 19.1–32.6%) for combination of lenvatinib and pembrolizumab versus placebo and pembrolizumab respectively. At the second interim analysis, the median OS was 15.0 months (95% CI: 13.2–17.0) for lenvatinib and pembrolizumab versus 17.9 months (95% CI: 13.8–21.6) for placebo and pembrolizumab (HR =1.15, 95% CI: 0.91–1.45; P=0.882); 61.4% of patients on the investigative arm had grade ≥3 treatment-related AEs (TRAEs) and 28% patients discontinued the treatment due to TRAEs. The investigators report 7 treatment-related deaths with the combination. The improvement in PFS and ORR failed to translate into improved OS and the numerically higher OS in the placebo arm highlights the potential toxicity with the combination.

The results of the trial by Saba et al. and LEAP-010 cannot be compared directly, however the outcomes are quite different with seemingly similar agents. Several potential explanations exist for the difference in outcomes: lower number of patients in Saba et al. trial due to a phase 2 design, lack of placebo-controlled arm, patient selection due to exclusion criteria, higher percentage of HPV, paranasal sinus and nasopharyngeal cancer patients, difference in toxicity management leading to lower rates of discontinuation of cabozantinib. There are also differences in the mechanism of action of lenvatinib (pan-VEGFR, FGFR1-4, PDGFRα, RET and c-KIT inhibitor) and cabozantinib (selective inhibitor of VEGFR2, MET and AXL inhibitor). Compelling outcomes with RR of 52%, 1-year PFS of 54% with a manageable safety profile, that translated to a median OS approaching 2 years, along with the elegant correlative results merit further evaluation of the combination of cabozantinib and pembrolizumab in a phase III trial.

Several combinations with immunotherapy have been explored with varied results and there are many ongoing trials. The combination PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab was compared to the EXTREME regimen in the phase 3 checkmate 651 trial and showed no statistically significant differences in OS [median OS: 13.9 versus 13.5 months with the investigative arm compared to the EXTREME regimen; hazard ratio (HR), 0.95; 97.9% CI: 0.80–1.13; P=0.4951] (11). The combination did show a favorable safety profile compared to the EXTREME regimen. Similarly, the phase 3 Kestrel trial evaluating the combination of PD-L1 inhibitor durvalumab with CTLA-4 inhibitor tremelimumab failed to show improved OS over the EXTREME regimen in frontline recurrent/metastatic setting (12). Monalizumab, targeting the natural killer group 2A, showed initial activity when combined with cetuximab and durvalumab (13,14) but confirmatory studies failed to demonstrate a benefit. Some of the other immunotherapy combinations with PD-1 inhibitors being explored include anti-CD47 antibody evorpacept (15,16), anti-TIGIT antibody, and anti-LAG-3 antibody (17).

The combination of anti-EGFR antibody cetuximab and pembrolizumab showed RR of 45% in a multicenter phase 2 study of 33 recurrent/metastatic HNSCC patients who were platinum refractory or platinum ineligible (18). A phase 2 trial of nivolumab and cetuximab showed a median OS of 20.2 months in previously untreated recurrent/metastatic HNSCC (19). Bispecific antibodies and antibody drug conjugates (ADCs) could represent promising approaches. Combination of bispecific anti-EGFR and anti-LGR5 antibody petosemtamab with pembrolizumab showed preliminary efficacy with an RR of 67% and safety in phase 1/2 trial and is being investigated in phase 3 trial (20). Bintrafusp alpha a bifunctional fusion protein targeting transforming growth factor beta (TGF-ꞵ) and PD-L1 showed a modest RR of 13% in previously treated HNSCC (21). ADCs like sacituzumab govitecan (22) which is a Trop-2-directed ADC linked to a topoisomerase inhibitor, enfortumab vedotin (23,24) or ADC directed to nectin-4, tisotumab vedotin (25) targeting tissue factor are being explored in early phase clinical trials with HNSCC cohorts and have the potential to move to frontline setting for recurrent/metastatic HNSCC in combination with pembrolizumab.

In conclusion, the phase 2 trial by Saba et al. showed unprecedented outcomes in HNSCC with the combination of immunotherapy and cabozantinib and highlight novel biomarkers like phosphorylated MET and CSF-1R for treatment selection. Several agents that look promising in non-randomized phase 2 trials fail to perform in larger, randomized phase 3 trials. However, if the results of the combination of cabozantinib and pembrolizumab hold up in a randomized phase 3 trial, it could lead to a new standard of care and significant improvement in outcomes for patients with metastatic/recurrent HNSCC.

Acknowledgments

None.

Footnote

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