Reshaping the Treatment Landscape for Recurrent/Metastatic Nasopharyngeal Carcinoma

In the context of checkpoint blockade in nasopharyngeal carcinoma, the results of the phase 3 RATIONALE-309 trial (NCT03924986) support earlier findings of the role immunotherapy may play for patients in the first line, according to Robert Haddad, MD, who spoke on the results in a discussion following the data presentation. Haddad is the chief, Division of Head and Neck Oncology, and McGraw Chair in Head and Neck Oncology at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School in Boston, Massachusetts.

“If you reserve immunotherapy for the second line vs [starting it in the] first line, does that make a difference? Based on the RATIONALE-309 study, it might actually be beneficial if you start patients on immunotherapy as part of their first-line treatment early in the disease course,” Haddad said.

During the discussion Haddad contextualized the results in comparison with outcomes seen with other immunotherapeutic agents combined with chemotherapy in the first line including toripalimab plus gemcitabine and cisplatin in the phase 3 JUPITER-02 trial (NCT03581786) and the addition of camrelizumab to gemcitabine and cisplatin in the phase 3 CAPTAIN-1st trial (NCT03707509).

Data from JUPITER-02 showed that treatment with toripalimab reduced the risk of disease progression by 48% compared with chemotherapy alone. The median PFS was 11.7 months (95% CI, 11-not estimable) among the 146 patients in the investigative arm vs 8.0 months (95% CI, 7.0-9.5) among the 143 patients in the placebo arm (HR, 0.52; 95% CI, 0.36 0.74; P = .0003).¹ The estimated 1-year PFS rates were 49.4% (95% CI, 36.4%- 61.1%) and 27.9% (95% CI, 18%- 38.8%), respectively.

In the CAPTAIN-1st trial, investigators observed a similar improvement in the firstline setting with the addition of camrelizumab to chemotherapy vs chemotherapy alone. The median PFS was 10.8 months (95% CI, 8.5-13.6) with the combination vs 6.9 months (95% CI, 5.9-7.9) with chemotherapy alone (HR, 0.51; 95% CI, 0.37-0.69; one-sided P < .0001). The 12-month and 18-month PFS rates were 45.8% and 34.8%, respectively, in the investigative arm compared with 20.5% and 12.7%, respectively, in the placebo arm.²

Although the studies were not powered for OS analysis, Haddad said, “We are seeing a trend in improvement in favor of the checkpoint inhibitor added to gemcitabine and cisplatin…really a robust result [and] it would be potentially helpful to combine these studies and [perform] a meta-analysis of the data for OS but these studies were not powered for OS and those results are not mature yet.”

Haddad said common themes between these studies included that they were similar in size, had similar hazard ratios for PFS, and that although the OS data were not mature they were trending in favor of adding checkpoint blockade to chemotherapy (Table^1,2,3). “Crossover [was] allowed [in these trials], which could potentially impact the OS,” Haddad said. “But, [similar to] what we saw in the RATIONALE-309 [results], despite that crossover we still saw a trend of improving OS with the triplet compared with the doublet.”

In terms of stratification based on PD-L1 expression, Haddad said it is important to note that the benefit with checkpoint inhibitors seems to be independent of PD-L1 status. “[This is] a signal we have seen repeatedly in studies where chemotherapy is combined with a checkpoint inhibitor; PD-L1 positivity seems to not matter as much in those types of studies [and] toxicity seems manageable,” he said.

Unanswered Questions in Metastatic Nasopharyngeal Cancer

Haddad added that there are unanswered questions remaining for the incorporation of triplet therapy for patients with metastatic disease, including for those with nonkeratinizing disease and undetectable or low Epstein-Barr virus (EBV) viral loads.

“[In] these studies [most] patients had nonkeratinizing nasopharyngeal carcinoma and tended to have EBV-related disease,” Haddad said. Among the patients in RATIONALE-309, 6.9% had keratinized disease and 19.8% had EBV levels below 500 IU/mL; in JUPITER-02, 1 patient had keratinizing squamous cell carcinoma and 37% of patients had a serum EBV copy number below 2000 IU/mL at baseline. Similarly, in CAPTAIN-1st, only 1 patient had keratinizing disease and 29% of patients had EBV-negative disease.

“Whether that benefit would translate to the [patients with] keratinizing carcinomas [and] non–EBV-related [disease], which we sometimes see in the Western world, remains to be determined but I have no reason to think it would not be beneficial also for those patients,” Haddad said.

In terms of the implications for these results in US-based practice, Haddad and Zhang highlighted that all 3 trials were conducted in China, where the incidence of nasopharyngeal carcinoma is much higher than in the US. However, the National Comprehensive Cancer Network (NCCN) has taken the results observed in these trials under advisement in a recent update to the head and neck cancer guidelines.⁴

“We had something unusual happen this year, based on the results of [the CAPTAIN-1st and JUPITER-02] studies; the NCCN adopted this combination of chemotherapy with a checkpoint inhibitor as an option for patients who have recurrent or metastatic disease,” Haddad said, pointing out that because camrelizumab and toripalimab are not available in the US, the NCCN recommends oncologists consider pembrolizumab (Keytruda) or nivolumab (Opdivo) in combination with gemcitabine/cisplatin for these patients. The NCCN still recommends gemcitabine/cisplatin alone as the preferred regimen in the first-line setting pending further information.⁴

Other questions Haddad noted were determining the optimal treatment duration as well as addressing sequencing questions. “[Do we give these agents for] 1 year, 2 years, or more? When you are dealing with metastatic cancer, is the checkpoint inhibitor important with gemcitabine/cisplatin when you start treatment? There was a separation of the [PFS] curves after 6 months when you compared [the combination] with placebo; is it then important to give the [checkpoint inhibitor] early on with gemcitabine/cisplatin or is better to give it later after gemcitabine/cisplatin? Unfortunately, I don’t think we have the answer right now based on these trials, but what we know right now is that these studies are telling us if you combine these 3 drugs early [then] you have a significant improvement in PFS.”

References

1. Mai HQ, Chen QY, Chen D, et al. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. Nat Med. 2021;27(9):1536-1543. Published correction in Nat Med. 2022;28(1):214
2. Yang Y, Qu S, Li J, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22(8):P1162-1174. doi:10.1016/S14702045(21)00302-8
3. Zhang L, Yang Y, Pan JJ, et al. RATIONALE-309: updated progression-free survival (PFS), PFS after next line of treatment, and overall survival from a phase 3 double-blind trial of tislelizumab versus placebo, plus chemotherapy, as first-line treatment for recurrent/ metastatic nasopharyngeal cancer. J Clin Oncol. 2022;40(suppl 36):384950. doi:10.1200/JCO.2022.40.36_suppl.384950
4. NCCN. Clinical Practice Guidelines in Oncology. Head and neck cancers, version 2.2022. Accessed April 28, 2022. bit.ly/38xlHVg