Pembrolizumab/Cabozantinib Combo Shows Promising Clinical Benefit in Recurrent Metastatic HNSCC

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Partner | Cancer Centers | <b>Winship Cancer Institute of Emory University</b>

Nabil F. Saba, MD, FACP, expanded on efficacy data from a phase 2 trial investigating pembrolizumab plus cabozantinib in patients with recurrent metastatic head and neck squamous cell carcinoma and current challenges and safety concerns in selecting patients for evaluation.

Data reported with pembrolizumab (Keytruda) plus cabozantinib (Cabometyx) demonstrated that the combination regimen is both highly active and well tolerated in patients with recurrent metastatic head and neck squamous cell carcinoma, indicating the need for further investigation of immuno-oncology- and antiangiogenic-based regimens in this population, according to Nabil F. Saba, MD, FACP.

Specifically, results presented at the 2022 ASCO Annual Meeting showed that the single-arm trial (NCT03468218) met its primary endpoint with an overall response rate (ORR) of 45.2% at the median follow-up, which was 12.7 months. Additionally, the median progression-free survival (PFS) was 14.6 months with the combination and the median overall survival (OS) was 22.3 months.

Furthermore, the clinical benefit rate was 90.4%. The 1-year OS rate was 67.7% (95% CI, 42.9%-83.6%), while the 1-year PFS rate was 51.8% (95% CI, 28.8%-70.7%).

“These [findings] are promising for a phase 2, single-arm trial, and raise the question of whether this combination could potentially improve [long-term] survival for patients with recurrent metastatic disease compared with single-agent pembrolizumab,” Saba said in an interview with OncLive®.

Saba is a professor and vice chair of quality and safety in the Department of Hematology and Medical Oncology, an adjunct professor in the Department of Otolaryngology, at Emory University School of Medicine, the Lynne and Howard Halpern chair of Head and Neck Cancer Research, and the co-director of Head and Neck Cancers in the Multi-Disciplinary Program at Winship Cancer Institute.

In the interview, Saba expanded on his presentation of efficacy data from the phase 2 trial, highlighting current challenges and safety concerns in selecting patients for evaluation, key trials investigating checkpoint inhibitors and multikinase TKI combinations in HNSCC, and the potential effects of new efficacy data on treatment strategies for this patient population.

OncLive®: What challenges do you experience in your treatment of patients with recurrent or metastatic HNSCC?

Saba: This disease is very difficult to treat, and historically has resulted in [low overall] survival. Data [preceding] the era of cetuximab [Erbitux]-based therapy [shows a] median overall survival around 6 months. This is a patient population in need of novel therapies.

[Additionally], most of these patients have [received] radiation or surgery [that has negatively] affected their outcomes and quality of life. [Recent studies of] HPV-related head and neck cancer [have demonstrated] some improvement in survival for these patients, but [the use of] immunotherapy and the approval of 2 PD-1 inhibitors a few years back [improved] the management of this disease and [helped] preserve quality of life. Still, improving survival for these patients [with both] HPV-related and unrelated [disease] is a big challenge.

What was the rationale for investigating cabozantinib in combination with pembrolizumab in patients with recurrent or metastatic HNSCC?

There are several [reasons] why we chose to proceed with this combination [strategy]. We have known for quite some time that VEGF inhibition does lead to immuno-modulatory effects on the cancer, so it made sense that an immuno-therapeutic approach could potentially involve VEGF inhibition.

Previous ECOG trials also [showed] that VEGF inhibitors [such as] bevacizumab [Avastin] do improve PFS for patients when it’s added to chemotherapy. Cabozantinib, which is the drug that we use in this trial, does have immunomodulatory effects on the tumor microenvironment in addition to VEGF inhibition.

Multikinase inhibitors combined with immunotherapeutic drugs have successfully improved outcomes for patients [with] different diseases, [such as] cabozantinib and nivolumab [Opdivo] in renal cell carcinoma. In addition to this, cabozantinib inhibits MET, which may play a role in EGFR resistance. [Lastly,] we know that one of the approved agents in head and neck metastatic disease is cetuximab. [Together, these facts indicate that] this strategy could prove valuable for patients.

What would you like to convey about the patient population?

When we planned this study, we [originally] wanted to look at patients who have not had any exposure to immunotherapy. We debated whether we should [limit the study population] to patients who are restricted to first-line therapy but would otherwise fulfill criteria for the extreme regimen. In the phase 3 KEYNOTE-040, phase 3 KEYNOTE-048, and the phase 2 KEYNOTE-055 trials with single-agent pembrolizumab, the ORR was around 18%. Since ORR was our primary endpoint, it did not seem reasonable to restrict inclusion to first line vs second line at this stage. We included patients with untreated recurrent/metastatic disease, provided they had not received PD-1 inhibitors [in previous lines of] treatment. Ultimately, most patients [did not have prior treatment; there was [perhaps] 1 patient who received prior platinum-based therapy in the recurrent metastatic setting.


Were there any caveats to consider when selecting patients for this trial?

Squamous cell carcinoma [requires clinicians to be] very careful about safety data when [considering] a VEGF inhibitor. When we designed the trial, we were careful to make sure that we excluded any patients who had contraindications to VEGF inhibition, any tumors encasing major blood vessels, any history of bleeding or clotting, and any cavitating lesions. Quite a few patients needed to be excluded based on that. [About] 14 out of 36 patients had to be excluded based on [these exclusion criteria.]

What is unique about the efficacy data with the combination of cabozantinib and pembrolizumab?

Historically, the response rate of single-agent pembrolizumab is [low for patients with R/M HNSCC.] Even if you focus on groups with high combined positive score scores [who typically] benefit most from this [therapeutic], ORR hovers around 20%. When we designed the trial, we wanted to see how the combination [treatment] could improve [these low] responses.

[Our trial had an] ORR exceeding 50%, which is a strong [indicator] of clinical efficacy.

What are the notable safety data from this study?

We did not observe evidence of major added toxicities when we used cabozantinib or pembrolizumab in combination that go beyond what we expect with them as single agents. This is because they have different toxicity profiles, and it makes sense to combine 2 classes of agents that would be easier on patients.

Thirteen patients on cabozantinib [required] dose reductions from 40 to 20 milligrams. We [performed an] analysis to see if there was any difference in outcome [due to dose reduction], and it doesn't seem to affect the clinical benefit of cabozantinib. [This aligns] with what is observed in other tumor types, such as renal cell carcinoma.

Tolerability is very important when [considering approaches] for patients [who] need to stay on [treatment] for an extensive period of time. In this trial, we did allow dose reduction for grade 2 or higher toxicities precluding continuation of the [combination regimen]. Overall, the treatment was well tolerated, provided we safeguard these factors.

Given the efficacy data emerging from this trial, how could this combination affect the treatment landscape for patients with HNSCC?

The ORR [we obtained] is a [great] start, but we're interested in improving [this] response for our patients. The response rate observed in this [trial], and [with] other TKIs [plus] PD-1 inhibitor [combinations] is somewhat equivalent to the response rate of chemoimmunotherapy that was observed on KEYNOTE-048. However, the potential for [this combination therapy] to completely replace chemotherapy still remains to be seen.

More importantly, we observed a generous PFS benefit [in patients receiving the combination therapy], exceeding the PFS we observed in KEYNOTE-048. These data signal that [TKIs plus immunotherapy] may produce more durable responses.

We are [currently] analyzing data looking at the duration of response. Overall survival (OS) was also generous in this cohort of patients, with close to 70% [alive at] 1 year.

What are the next steps for investigating multikinase and immune checkpoint inhibitor combinations in this patient population?

If we want to focus on recurrent metastatic disease, we need to closely observe TKI and PD-1 inhibitor combinations over the next [few] years. I would not be surprised if this changes the standard of care for patients with first-line recurrent metastatic disease. Sequencing of therapies is also important [to determine if patients should employ] a VEGF inhibitor with chemotherapy after failing a PD-1 inhibitors, or resort back to EGFR inhibition with [added] cytotoxic therapy.

Efforts [to investigate] MET inhibitors in HPV-negative disease, [such as a phase II trial (NCT03422536) evaluating the anti-HGF mAb] ficlatuzumab in combination with cetuximab, [are] very intriguing. [These studies] tell us that treatment strategies for the HPV-negative group seem to be diverging from the HPV-positive group. The great thing about the cabozantinib and pembrolizumab data, which probably would apply to other TKIs, is that we're seeing benefit across [both] HPV-positive and HPV-negative disease types.

[This benefit] also seems to occur regardless of [the presence of] any specific biomarkers, and for both high and low CPS scores. [These data could imply that TKIs] are changing the equation when we combine them with PD-1 inhibitors.

The other [area of focus for current] clinical trials of HPV-related disease in the recurrent metastatic setting [is] targeting HPV-specific proteins through vaccination.

What other trials within HNSCC would you like to highlight?

There have been a couple of trials showing that the combination of PD-1 inhibitors with cetuximab is also a winning strategy. It seems that this combination is more likely [to be] efficacious in the HPV-unrelated cohort of patients, which is not surprising given the role of EGFR in this disease.

Along those lines, we are waiting for data from the phase 3 LEAP-010 trial [NCT04199104], which is randomizing patients to single-agent pembrolizumab vs pembrolizumab and lenvatinib. [This trial] will be important [in evaluating] whether [TKI and immunotherapy combinations are effective] in other disease types.

These are very exciting data [which could] change the standard of care [for recurrent metastatic HNSCC]. The observations my colleagues and I [gathered from] this study encouraged us to promote this combination. [Although] it's not a standard combination, it is certainly something to watch.


Saba NF, Ekpenyong A, McCook-Veal A, et al. A phase II trial of pembrolizumab and cabozantinib in patients (pts) with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). J Clin Oncol. 2022;40(suppl 16):S6008. doi:10.1200/jco.2022.40.16_suppl.6008