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BeiGene Updates Phase III Data, Biomarker Analysis for Anti-PD-1 Drug in Nasopharyngeal Cancer

NEW YORK – Nasopharyngeal cancer patients with "hot" gene expression signatures had the greatest progression-free survival advantage with BeiGene's anti-PD-1 inhibitor tislelizumab and chemotherapy in a Phase III trial, the company reported on Tuesday in an American Society of Clinical Oncology Plenary Series presentation.

As part of a presentation to discuss updated results from the RATIONALE-309 trial, Li Zhang of the Sun Yat-Sen University Cancer Center said that this gene signature may be a biomarker for predicting best responders to the tislelizumab-chemo regimen, though further research is warranted.

Globally, 133,000 patients are diagnosed with nasopharyngeal cancer (NPC) each year, and 80,000 die from it. The disease is widespread in Asia, and the prognosis for patients with recurrent and metastatic disease remains poor.

The RATIONALE-309 trial is a double-blind, placebo-controlled Phase III trial that has randomized 263 recurrent or metastatic NPC patients in China, Taiwan, and Thailand to receive either tislelizumab with gemcitabine and cisplatin or a placebo and gemcitabine-cisplatin as a first-line treatment. Its primary endpoint is progression-free survival, and secondary endpoints include duration of response, overall survival, and time to second objective disease progression (progression-free survival 2).

The updated results for the trial line up very closely with its interim results, which BeiGene reported in December at the European Society for Medical Oncology Immuno-Oncology Congress. In the overall population, regardless of biomarker status, the interim analysis yielded a median progression-free survival of 9.2 months in the tislelizumab arm, compared with 7.4 months in the placebo arm. The updated progression-free survival analysis came in at 9.6 months for patients on tislelizumab and chemo, and 7.4 months again for those on placebo and chemo.

According to Zhang, there was a numerical overall survival benefit in the active therapy arm, but median overall survival had not been reached. In the placebo arm, median overall survival was 23 months. This result, in the all-comer population, "indicated that tislelizumab plus chemotherapy should be used in the first line to deliver the maximum clinical benefit," said Zhang.

Next, researchers considered patient outcomes according to specific biomarker subgroups. Ninety-one percent of study participants were evaluable for PD-L1 expression using immunohistochemistry testing and 94 percent had gene expression profiling on the HTG EdgeSeq Precision Immuno-Oncology Panel, which sequences 1,392 genes related to tumor-immune system interactions.

It turned out that patients in the tislelizumab arm experienced a progression-free survival benefit over the placebo arm regardless of PD-L1 expression. However, gene expression profiling identified three patient clusters with "cold," "medium," or "hot" tumor microenvironments.

Zhang said that the cold cluster was characterized by the highest tumor proliferation rate and a low immune profile. The medium cluster had the highest expression of interferon gamma, macrophage, and fibroblast gene signatures. And the hot cluster tumors had the highest expression of immune cells, including T cells, NK cells, and dendritic cells.

Upon further analysis, the activated dendritic cells were the most important cell population associated with the treatment effect. Drilling deeper into the genes associated with that effect, they found that lysosome-associated membrane glycoprotein 3, which Zhang called a "classic" dendritic cell activation marker, was the most significant gene associated with progression-free survival benefit on tislelizumab.

"Dendritic cell activation was positively correlated with progression-free survival benefit and may serve as a potential biomarker for predicting efficacy," Zhang said. "Further research is warranted."

While Zhang did not break out the progression-free survival data in the three patient clusters, BeiGene said in a statement that "the greatest progression-free survival benefit of tislelizumab in combination with chemotherapy was observed in patients exhibiting 'hot' tumor microenvironment profiles."

With clear benefits for progression-free survival and a probable overall survival benefit in the overall population, Zhang said the trial results indicate that tislelizumab plus chemotherapy may become the standard first-line therapy for patients with recurrent or metastatic NPC.

The positive results from RATIONALE-309 may also have implications beyond tislelizumab, according to Robert Haddad of the Dana-Farber Cancer Institute, who gave a presentation on the impact of checkpoint inhibitors in NPC in the plenary session.

According to Haddad, RATIONALE-309 is one of three Phase III clinical trials to show that adding a checkpoint inhibitor to standard treatment benefits NPC patients. The JUPITER-02 Phase III trial, for example, showed that Junshi Biosciences' toripalimab with gemcitabine-cisplatin extended progression-free survival compared to just chemo as a first-line therapy for recurrent or metastatic NPC. And the Captain-1st Phase III trial gave similar results for Jiangsu HengRui Medicine's camrelizumab plus gemcitabine-cisplatin.

Haddad said the findings from JUPITER-02 and Captain-1st were compelling enough that the National Comprehensive Cancer Network now supports the use of a checkpoint inhibitor with chemo as a treatment for recurrent and metastatic NPC. However, since toripalimab and camrelizumab are not available in the US, NCCN recommends Bristol Myers Squibb's Opdivo (nivolumab) or Merck's Keytruda (pembrolizumab) in combination with gemcitabine-cisplatin.

"I believe that gemcitabine and cisplatin plus a checkpoint inhibitor represent a reasonable option to treat patients with recurrent metastatic NPC in that first-line setting," Haddad said. "The next step obviously would be to try to move these agents early on in the disease spectrum and test them in an induction chemotherapy setting … to test the notion of adding a checkpoint inhibitor to this platform for patients with curable nasopharyngeal carcinoma."

Most of the patients in the trial had non-keratinizing forms of NPC that were related to the Epstein-Barr virus. It is unclear whether or not the benefits seen in the trial would extend to keratinizing, non-EBV forms of NPC that are less uncommon in the West. "I have no reason to think it would not be beneficial for those patients," said Haddad.

Tislelizumab is already approved in China for advanced squamous and non-squamous non-small cell lung cancer, Hodgkin lymphoma, high PD-L1-expressing metastatic urothelial carcinoma, and hepatocellular carcinoma. The Beijing-based firm has begun or completed 13 Phase III trials and four pivotal Phase II trials for the drug and is developing it against a range of cancers.

In January 2021, BeiGene signed a collaboration and licensing agreement with Novartis for development of tislelizumab in North America, Europe, and Japan. The US Food and Drug Administration is reviewing a biologics license application for tislelizumab as a treatment for unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma.