Toripalimab Approval Pioneers Immunotherapy Use in Nasopharyngeal Cancer

Nabil F. Saba, MD, FACP

Toripalimab-tpzi (Loqtorzi) has entered the nasopharyngeal carcinoma treatment arena as the first approved PD-1 inhibitor for patients with treatment-naive or recurrent disease, according to Nabil F. Saba, MD, FACP, and Shravan Kandula, MD.

On October 27, 2023, the FDA approved the combination of toripalimab, gemcitabine, and cisplatin for the first-line treatment of adult patients with recurrent or metastatic locally advanced nasopharyngeal cancer, based on findings from the phase 3 JUPITER-02 trial (NCT03581786).¹ Toripalimab was also approved as monotherapy in the recurrent or metastatic setting for adult patients with nasopharyngeal carcinoma who experienced disease progression on or after platinum-based chemotherapy, based on findings from the phase 2 POLARIS-02 trial (NCT02915432).

“Given the provocative overall survival [OS] and progression-free survival [PFS] benefits [with toripalimab vs standard of care [SOC] in the context of a phase 3 randomized study, the combination of toripalimab plus cisplatin and gemcitabine should be the SOC in the population [of patients] with recurrent/metastatic nasopharyngeal carcinoma, as the data are truly practice changing,” Kandula said in an interview with OncLive^®.

“I look forward to the next few years as an exciting time for nasopharynx cancer and head and neck cancer overall,” Saba added in the interview.

In the interview, Saba and Kandula highlighted the significance of the approval of toripalimab; key data from JUPITER-02 and POLARIS-02; and how the addition of this agent to the treatment armamentarium heightens the importance of multidisciplinary collaboration.

Saba is a professor and vice chair for Quality and Safety in the Department of Hematology and Medical Oncology and an adjunct professor in the Department of Otolaryngology at Emory University School of Medicine, as well as The Lynne and Howard Halpern Chair in Head and Neck Cancer Research and codirector of the Head and Neck Cancer Multidisciplinary Program at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

Kandula is a radiation oncologist at AdventHealth Medical Group Radiation Oncology at Central Florida in Orlando.

OncLive: What is the mechanism of action of toripalimab?

Saba: We live in an exciting time when it comes to immunotherapy in the management of oncologic diseases, head and neck cancer in particular, and more specifically, nasopharyngeal carcinoma, because we’ve witnessed a major change in the indications [in] this disease as far as immunotherapeutic applications. Toripalimab falls under that category. It is a PD-1 inhibitor that has been developed [outside the United States] and tested in nasopharynx cancer in 2 major trials: the POLARIS-02 trial and, more recently, the JUPITER-02 trial, both of which have resulted in interesting outcomes.

[Although toripalimab] is a PD-1 inhibitor, it’s important to recognize that the exact mechanisms of action of many PD-1 inhibitors may not be equivalent to each other. For example, the binding sites for nivolumab and pembrolizumab on the PD-1 molecule are different. Toripalimab binds on the FG portion of the loop, and [it has] a potentially stronger inhibition of PD-1 compared with [that of] other PD-1 inhibitors.

Kandula: Toripalimab is a humanized PD-1 monoclonal antibody that binds to PD-1 receptor T cells, which helps prevent the binding of PD-1 with the ligands on cancer cells. That helps restore antitumor immunity. Blocking this interaction upregulates our own immune system’s ability to kill and attack cancer cells. Most nasopharyngeal carcinomas are PD-L1 expressing, so it’s beneficial to have an immunotherapy agent like toripalimab in this population.

What is the significance of the FDA approval of toripalimab for patients with nasopharyngeal carcinoma?

Kandula: The phase 3 JUPITER-02 study demonstrated that first-line treatment with toripalimab plus gemcitabine and cisplatin yielded a clinically meaningful improvement in OS and PFS compared with gemcitabine and cisplatin alone in patients with recurrent or metastatic nasopharyngeal carcinoma, with 30.1 months of follow-up data.² The 3-year OS rate was 65.1% in the combination arm, with a median PFS of 21.4 months compared with 8.2 months with chemotherapy alone, which is a substantial improvement and solidifies this regimen as a new SOC in this patient population.

How does toripalimab address unmet needs for patients with nasopharyngeal carcinoma?

Saba: The main unmet need is that patients with recurrent metastatic disease have a poor prognosis. This agent, in addition to other PD-1 inhibitors, stands to change the SOC.

Kandula: We cure many patients with locally advanced nasopharyngeal carcinoma using SOC induction gemcitabine [plus] cisplatin followed by chemoradiation. However, 20% of those patients still progress locoregionally and/or distantly [within] 5 years [of follow-up]. Traditionally, these patients have been treated with gemcitabine or cisplatin salvage chemotherapy.

However, that regimen has only yielded a median PFS of [approximately] 7 months, with a median OS of approximately 29 months. By 3 years, only 30% of patients are living on that regimen. Many of the trials that led to the approval of other immunotherapy drugs in recurrent head and neck cancer specifically excluded [patients with] nasopharyngeal carcinoma. JUPITER-02 addressed an unmet need of patients [in this] population who experience recurrence after curative-intent therapy.

What key efficacy findings read out from JUPITER-02?

Saba: JUPITER-02 is 1 of several phase 3 trials that have targeted patients with recurrent, metastatic nasopharyngeal carcinoma. [This trial] added a PD-1 inhibitor to the backbone of gemcitabine and platinum-based therapy because gemcitabine and platinum therapy was deemed superior to other chemotherapeutic interventions in this patient population. JUPITER-02 added toripalimab to the combination and resulted initially in an impressive improvement in PFS, with the standard arm having a median PFS of 8.0 months vs 11.7 months in the toripalimab arm. At the 2023 ASCO Annual Meeting, we saw more mature PFS data. The experimental arm had an impressive median PFS of 21.4 months. The difference [in median PFS] between the control arm and the experimental arm reached 13.2 months.

We also saw data [in the first-line setting showing an] improvement in OS [with toripalimab]. That was expected, but in this patient population, the OS may take more time to mature given the nature of the disease, its responsiveness to therapy, and the relative survivability of these patients, even in the recurrent/metastatic setting. However, there was a statistically significant improvement in OS [with the toripalimab combination] with a hazard ratio of 0.63.

[The FDA decision, which was] in favor of [the toripalimab] combination, has completely changed the SOC for this disease in [the United States]. [Before this approval, there was] no approved PD-1 inhibitor in combination with gemcitabine and cisplatin [for patients with nasopharyngeal carcinoma].

At least 3 major trials are investigating combinations [of PD-1 inhibitors and chemotherapy in patients with nasopharyngeal carcinoma]. We mentioned JUPITER-02, [and there is also the phase 3] CAPTAIN-1st trial [NCT03707509] using another PD-1 inhibitor, camrelizumab. The [phase 3] RATIONALE-309 trial [NCT03924986] is using another PD-1 inhibitor, tislelizumab [Tevimbra]. Impressively, those 3 different PD-1 inhibitors, when combined with the backbone of gemcitabine and platinum [chemotherapy], result in an improvement in PFS [vs chemotherapy alone]. Another trial, which uses yet another PD-1 inhibitor, penpulimab, is currently accruing.

I suspect we will be busy over the next few years trying to decipher which of these trials will gain momentum in terms of the approvability [of their respective agents]. We live in an exciting time in nasopharynx cancer, so we may end up with different options of PD-1 inhibitors. We still don’t have a lot of OS data maturing for these other trials. JUPITER-02 seems to be the leading trial in terms of OS data. [The FDA approval of toripalimab] may open the door for the other [PD-1 inhibitors] to move forward in other indications.

What were the key efficacy data from the POLARIS-02 trial?

Saba: The POLARIS-02 trial tested toripalimab as a single agent in patients who progressed on systemic therapy for nasopharynx cancer. We have to put it within the context of what has happened with PD-1 inhibitors as single agents in this disease. The most widely used PD-1 inhibitors, nivolumab [Opdivo] and pembrolizumab [Keytruda], [elicit] response rates of approximately 20% to 25%.

The POLARIS-02 study showed us an overall response rate [ORR] rate of 20.5% [with toripalimab].³ It had 190 patients [who] were pretreated. They never had prior immunotherapy; however, they had progressed on systemic cytotoxic therapy and had recurrent/metastatic disease. The ORR was not surprising, but the median duration of response was generous, at 12.8 months, and the median PFS was 1.9 months.

It’s also interesting that the patients who had PD-L1–positive disease appeared to have enriched responses [to toripalimab, with an ORR of 27.1%], which is something we did not see translate into the JUPITER-02 trial. We did not see a significant correlation with PD-L1 [status and responses to toripalimab plus chemotherapy] in JUPITER-02 or other phase 3 trials, whereas with single-agent [toripalimab], this seems to be a different story.

The POLARIS-02 study demonstrated manageable toxicity and efficacy [with toripalimab], and that led initially to the FDA providing a breakthrough designation for toripalimab in nasopharyngeal carcinoma. The JUPITER-02 data are more definitive as that is a randomized phase 3 trial.

What is the safety profile of toripalimab?

Saba: The safety profile of toripalimab is what you would expect with PD-1 inhibitors, which are much less toxic than cytotoxic chemotherapy. You would expect the usual toxicities within the head and neck cancer cohort of patients, namely thyroid dysfunction in some patients, but rare toxicities could also happen. We have to be on the lookout for the serious toxicities that, thankfully, are less common.

The adverse effect [AE] profile was favorable for toripalimab [in the] POLARIS-02 study. That’s 1 of the reasons why the FDA granted it a breakthrough designation [and later approval]. In the JUPITER-02 trial, there was nothing alarming in terms of the tolerability of the combination. [Those data] seem to show us a toxicity [profile of toripalimab that is] along the same paths as [that of] other PD-1 inhibitors.

How does this approval affect standard radiation oncology practices for patients with nasopharyngeal carcinoma?

Kandula: With locally recurrent nasopharyngeal carcinoma following chemoradiation, it can be difficult to offer resection or safely deliver a course of re-irradiation, given the anatomical location [of the disease]. Prior studies have demonstrated that 20% to 40% of deaths in patients with locally regional recurrent nasopharyngeal carcinoma were attributed to treatment-related AEs, specifically nasal hemorrhage, [which is] 1 of the more common grade 5 AEs we see. We always like to offer a salvage curative-intent therapy, but a safe cure may be difficult to achieve given the location [of the disease]. The results from JUPITER-02 indicate that the combination of toripalimab and chemotherapy may provide a more sanguine option for patients. Radiation oncologists and medical oncologists may not necessarily want to risk serious and even fatal toxicities with re-irradiation.

With the addition of toripalimab to the nasopharyngeal carcinoma treatment paradigm, what is the importance of multidisciplinary collaboration between medical oncologists, radiation oncologists, and other teams?

Saba: [Toripalimab] is an added tool for medical oncologists to use for patients who have recurrent/metastatic nasopharyngeal carcinoma. [Before this approval], our go-to plan was to look for any clinical trials that were available for these patients, because that is always on the top of our priorities. However, with a lack of clinical trials, this [approval] opened the door for novel treatment for patients with recurrent/metastatic disease.

There is also interest in exploring PD-1 inhibitors in the definitive therapy setting. At the 2023 ASCO Annual Meeting, we saw results from the [phase 3] CONTINUUM trial [NCT03700476], which is adding yet another PD-1 inhibitor, sintilimab, to the backbone of sequential therapy with gemcitabine/platinum followed by platinum and radiation. Early results show that [treatment with] the PD-1 inhibitor resulted in a significantly improved event-free survival rate at 3 years.

The collaboration with other head and neck specialists, including radiation oncologists, will [evolve] over time, given that [PD-1 inhibitors] will no doubt reach the definitive therapy setting. It would not be surprising if [the results from CONTINUUM] lead to an approval [of sintilimab], once we get more mature data. The field is moving at a rapid pace, specifically in nasopharynx cancer. Ten years ago, none of this was on the horizon, and in a short period of time, we have all of this happening.

Kandula: Radiation oncologists, medical oncologists, and head and neck surgeons typically follow patients [with nasopharyngeal carcinoma] longitudinally with clinical exams, imaging, and Epstein-Barr virus DNA titers to monitor for recurrence. It’s important for all members of the multidisciplinary team to be aware of the [JUPITER-02] data, as any team member can refer [patients] to medical oncologists for toripalimab if they see an eligible patient. It’s important to discuss these patients, ideally in a multidisciplinary tumor board, to make the most appropriate treatment decisions and determine [whether patients can] achieve a safe, salvage curative-intent therapy or [whether] they [will be] better served by systemic therapy with toripalimab, gemcitabine, and cisplatin.

What does the future look like for the management of nasopharyngeal cancer?

Saba: The approval [of toripalimab] opens the door for a bigger question in terms of how the FDA will deal with approving agents that have been developed [outside the United States]. It will be interesting to see how that will play out in terms of indications and treatment options for patients. This is, from a patient standpoint and a physician standpoint, an exciting time, because the more options we have, the better. [These options may improve financial circumstances and patients’] overall prognosis and health-care delivery. I look forward to seeing all these changes happening for toripalimab and for other agents, as well.

References

1. Coherus and Junshi Biosciences announce FDA approval of Loqtorzi (toripalimab-tpzi) in all lines of treatment for recurrent or metastatic Nasopharyngeal carcinoma (NPC). News release. Coherus BioSciences and Shanghai Junshi Biosciences. October 27, 2023. Accessed November 6, 2023. https://www.globenewswire.com/news-release/2023/10/27/2768663/0/en/Coherus-and-Junshi-Biosciences-Announce-FDA-Approval-of-LOQTORZI-toripalimab-tpzi-in-All-Lines-of-Treatment-for-Recurrent-or-Metastatic-Nasopharyngeal-Carcinoma-NPC.html
2. Mai H-Q, Chen Q-Y, Chen D-P, et al. Final overall survival analysis of JUPITER-02: a phase 3 study of toripalimab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC). J Clin Oncol. 2023;41(suppl 16):6009. doi:10.1200/JCO.2023.41.16_suppl.6009
3. Wang FH, Wei XL, Feng J, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02). J Clin Oncol. 2021;39(7):704-712. doi:10.1200/JCO.20.02712