乌鸦传媒

Adding the PD-L1 inhibitor avelumab (Bavencio) to standard chemoradiotherapy (CRT) for locally advanced head and neck cancer failed to improve progression-free survival (PFS) in a randomized trial.

Median PFS was not reached in patients who received avelumab or placebo during and after CRT. The lower limit of the 95% confidence intervals actually favored the placebo arm (23.0 vs 16.9 months).

Safety profiles were similar for the two treatment arms, Nancy Y. Lee, MD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors reported in .

"What's concerning to me is that it's one thing to be negative, which means it didn't help, but the [survival] curves actually separated in favor of placebo," Lee told 乌鸦传媒. "This was highlighted on Twitter and it went viral and people are concerned. The good thing is that we are doing all of the correlative studies we need to know why, mechanistically."

"We know that chemoradiation can cure cancer; it can cure head and neck cancer," she added. "The crazy thing here is we actually had an antagonistic effect, which I don't quite understand. What's also weird to me is that we gave 1 year of adjuvant immunotherapy after chemoradiation [like the positive PACIFIC trial in lung cancer]. Let's say that we kill the T-cells with chemoradiation, but after 1 year of immunotherapy the T cells recover. Except they didn't and people still did poorly. It's a mystery to me."

Immune checkpoint inhibitors have approval for treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, data for use of the agents in locally advanced disease remained scarce, the researchers noted. A literature search encompassing publications through mid-2020 identified two phase I/II trials of immune checkpoint inhibitors for locally advanced HNSCC.

The current standard of care for unresected locally advanced HNSCC is high-dose cisplatin-based CRT or radiotherapy plus carboplatin-fluorouracil or cetuximab (Erbitux) for patients who are ineligible for cisplatin-based therapy. Five-year overall survival (OS) remains poor -- about 50% for late-stage disease, the authors continued.

Both chemotherapy and radiotherapy modulate the tumor microenvironment by inducing immunogenic cell death and upregulating tumor PD-L1 expression, offering the potential for synergistic activity when combined with immunotherapy.

A strategy of following CRT with immunotherapy significantly improved OS in stage III unresectable non-small cell lung cancer in the PACIFIC trial. Lee and colleagues evaluated the strategy in the phase III .

The study involved 697 patients with untreated locally advanced HNSCC (oropharynx, hypopharynx, larynx, or oral cavity). Investigators in 22 countries randomized the patients to receive avelumab or placebo plus CRT followed by 1 year of adjuvant avelumab or placebo.

The primary endpoint was investigator-assessed PFS. Median follow-up was 14.5-15.0 months in each treatment group.

At the time of data analysis, median PFS had yet to be reached in either treatment group. Nevertheless, the hazard ratio for disease progression or death represented an unfavorable trend for the avelumab group (HR 1.21, 95% CI 0.93-1.57).

The most common grade ≥3 treatment-related adverse events in the avelumab and placebo groups were neutropenia (16% vs 15%), mucosal inflammation (14% vs 13%), dysphagia (14% in both groups), and anemia (12% vs 13%). Serious adverse events occurred in 36% of patients allocated to adjuvant avelumab and 32% to the placebo arm.

The door has not yet closed on adjuvant immunotherapy for locally advanced HNSCC, as an ongoing trial with a similar design is evaluating pembrolizumab. Trials in other types of cancer also are ongoing. Lee urged caution in moving forward with the strategy.

"We have all of these ongoing trials right now, and they all combine immunotherapy with chemotherapy and radiation or immunotherapy with radiation only," she said. "I think we really need to think twice about the ongoing trials and be careful."

"We have to think about how we can incorporate immunotherapy," Lee noted. "There are some ongoing trials right now where all we do is adjuvant immunotherapy. Right now we know one thing: We can't give it during radiation."

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