PD-L1 Status Could Help Inform Patient Selection for IO-Based Therapy in HNSCC

Ranee Mehra, MD, discusses the significance of 5-year follow-up data and the subgroup analysis from KEYNOTE-048, the benefits and limitations of IO therapy in head and neck squamous cell carcinoma, and research aiming to expand the role of IO combination regimens in this space.

Ranee Mehra, MD.

Ranee Mehra, MD.

The efficacy of pembrolizumab (Keytruda) alone or in combination with chemotherapy increased with higher PD-L1 expression as frontline treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who were enrolled in the phase 3 KEYNOTE-048 trial (NCT02358031), according to a subgroup analysis of the study. However, more research is needed to better identify patients with HNSCC who could benefit from immune-oncology (IO)–based therapy, according to Ranee Mehra, MD.

“A patient’s PD-L1 expression and clinical status [are important to] use in determining a first-line regimen, whether it’s with chemotherapy in combination with IO, [or just] IO monotherapy,” Mehra said following a presentation on IO therapy for HNSCC at the 40th Annual CFS® meeting. “Involving a patient’s individual factors is important in the initiation of treatment, as well as in decisions about whether [an agent] needs to be added or reduced for toxicity.”

In the interview with OncLive®, Mehra discussed the significance of 5-year follow-up data and the subgroup analysis from KEYNOTE-048, the benefits and limitations of IO therapy in HNSCC, and several areas of research aiming to expand the role of IO combination regimens in this space. Mehra is a professor of medicine and the director of Head and Neck Medical Oncology at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center.

OncLive®: Could you provide a brief overview of your presentation on IO therapy within HNSCC?

Mehra: I started with a review of the KEYNOTE-048 data, including the updated 5-year survival data, which show that there is [a proportion] of patients who reach that tail of the curve where they have long-term survival. I also reviewed some of the subset analyses, especially with regard to PD-L1 expression, highlighting that the PD-L1–positive patients are the ones who have better outcomes with IO therapy, whether as monotherapy or [in combination] with chemotherapy.

I also touched on some data we are now seeing with regard to IO in combination with radiation. [This type of combination] has not shown as much effectiveness as we would have wanted, raising some questions in that space. Finally, I briefly touched on some emerging data [on] human papilloma virus [HPV]–directed therapy and tumor-infiltrating lymphocytes.

What do the long-term data from KEYNOTE-048 mean for this patient population?

Those data have completely changed the course of the disease, at least for the patients who are receiving long-term benefit. These are not all patients, and unfortunately, still a minority of patients become long-term survivors. However, those long-term survivors are [experiencing years of] survival. This was previously [possible]—even in the control arm there was a small percentage of patients who were long-term survivors. [Still,] we are seeing more patients living longer, with good quality of life and [without] excessive toxicity.

What is the rationale for the continued investigation of IO therapy in HNSCC?

We need better biomarkers to [improve patient selection] for IO monotherapy and to try to determine [which patients] may be long-term survivors up front. Additionally, we still need to learn how to enhance the effectiveness of [IO] treatment with rational combinations. We are still struggling as a field to select [the most appropriate] combinations for [specific] patient populations. either up front or in the refractory setting.

Research on IO plus radiation therapy has yielded minimal efficacy results thus far. How might researchers adjust their treatment strategies to maximize the benefits of this combination?

A lot of the trials [on IO plus radiation performed] to date have been in unselected patient populations. They’ve looked at PD-L1 retrospectively, but there hasn’t been strong selection. Perhaps incorporating some patient selection [could be beneficial]. Also, sequential approaches [for] either [before or after] radiation therapy could be investigated.

What are some future avenues for researching IO therapy in this space?

There has been interest [in studying] IO in combination with targeted therapies and multi-kinase inhibitors. Lenvatinib [Lenvima] and pembrolizumab is one regimen that’s currently being studied. There are [also] some cellular therapies specifically directed at HPV-positive disease [being investigated]. [Lastly], a lot of different IO agents are being looked at in phase 1 trials, so it’s just too early to get a clear signal about which ones might advance further.

Outside of IO therapy, are there any other areas of focus for HNSCC research that you would like to highlight?

We haven’t completely abandoned targeted therapy approaches [in HNSCC]. We know [that] up to 30% of patients have PIK3CA alterations, and there are programs specifically looking at [PI3K] inhibitors in this space. Knowing that not all patients benefit from IO [therapy], we do need to look at other strategies, especially as we’re learning more about the molecular biology of different genomic profiles.


Burtness B, Rischin D, Greil R, et al. Pembrolizumab alone or with chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048: subgroup analysis by programmed death ligand-1 combined positive score. J Clin Oncol. 2022;40(21):2321-2332. doi:10.1

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