Frontline SHR-1701 Plus CAPOX Delivers Superior OS vs CAPOX Alone in Gastric/GEJ Cancer

Zhi Peng, MD

The bifunctional PD-L1/TGF-β-directed agent SHR-1701 may be one of the next therapeutic advances to improve personalized treatment for patients with HER2-negative gastric/gastroesophageal junction (GEJ) cancer, although further research is needed to accurately differentiate this agent from PD-1 inhibitors, according to Zhi Peng, MD. 

Previously, data from a phase 1 dose-escalation, dose-expansion, and clinical-expansion study (NCT03710265) showed that SHR-1701 monotherapy demonstrated antitumor activity in patients with advanced solid tumors, particularly those with gastric cancer.¹ These findings supported the initiation of a multicenter, 2-part, phase 3 trial (NCT04950322) investigating SHR-1701 plus CAPOX (capecitabine and oxaliplatin) in patients with unresectable, locally advanced or metastatic, HER2-negative gastric/GEJ adenocarcinoma.

Results from this phase 3 study were presented at the 2024 ESMO Congress. In the intent-to-treat (ITT) population, the median overall survival (OS) was 15.8 months (95% CI, 14.0-16.9) with SHR-1701 plus CAPOX (n = 365) vs 11.2 months (95% CI, 9.4-12.1) with placebo plus CAPOX (n = 366; HR, 0.66; 95% CI, 0.53-0.81; 1-sided P < .0001).² Among patients with a PD-L1 combined positive score (CPS) of at least 5, the median OS was 16.8 months (95% CI, 14.7-not reached) with SHR-1701 plus CAPOX (n = 246) vs 10.4 months (95% CI, 9.0-12.1) with placebo plus CAPOX (n = 248; HR, 0.53; 95% CI, 0.40-0.68; 1-sided P < .0001).

The addition of SHR-1701 to CAPOX also improved progression-free survival (PFS) outcomes by blinded independent central review. In the ITT population, SHR-1701 plus CAPOX led to a median PFS of 7.0 months (95% CI, 6.6-8.3) vs 5.5 months (95% CI, 5.1-5.6) with placebo plus CAPOX (HR, 0.57; 95% CI, 0.48-0.69). In patients with a PD-L1 CPS of at least 5, the median PFS was 7.6 months (95% CI, 6.5-9.3) with SHR-1701 plus CAPOX vs 5.5 months (95% CI, 4.4-5.6) with placebo plus CAPOX (HR, 0.52; 95% CI, 0.42-0.66).

“In the future, [regulatory agencies in] China may approve SHR-1701 plus CAPOX for the first-line [management of] HER2-negative gastric cancer,” Peng said in an interview with OncLive® regarding this dataset.

In the interview, Peng discussed the unique features of SHR-1701, key efficacy findings from this phase 3 trial, and how future research may answer questions regarding the role of SHR-1701 in the gastric/GEJ cancer treatment paradigm.

Peng is an associate professor at Beijing Cancer Hospital, Peking University, as well as a medical oncologist in the Key Laboratory of Carcinogenesis and Translational Research ministry in the Department of Gastrointestinal Oncology at the Peking University Cancer Hospital & Institute in Beijing, China. 

OncLive: What is the mechanism of action of SHR-1701?

Peng: SHR-1701 is a bifunctional antibody that blocks both TGF-β and the PD-1/PD-L1, pathway. TGF-β is an inhibitor of the [antitumor functions of immune cell populations in the tumor] microenvironment. We want to block TGF-β to enhance the [efficacy of agents directed toward the] PD-1 pathway so they can treat gastric cancer.

What was the design of this phase 3 trial?

In 2021, we initiated this phase 3 clinical trial with a safety run-in part. In the randomized, double-blind [portion of the] trial, patients were randomly assigned to receive SHR-1701 or placebo [for up to 2 years] plus CAPOX for up to 6 cycles. The primary end point is OS [in the population of patients with a] PD-L1 CPS of 5 or higher and in the ITT population.

What key efficacy findings from this trial were presented at ESMO?

Both in the PD-L1 CPS 5 or higher and ITT populations, SHR-1701 [plus CAPOX] improved both the PFS and the OS [compared with chemotherapy plus CAPOX]. The HR [for OS in the ITT arm was] 0.66. The ORR was also improved in the SHR-1701 arm.

What is the safety profile of SHR-1701?

This antibody is safe. In both arms of the phase 3 trial, the treatment-related adverse effects [TRAEs] were similar to each other. [The rates of] TRAEs of grade 3 or higher were [62.6% in the SHR-1701 arm vs 59.0% in the placebo arm]. Additionally, the rates [of TRAEs] leading to death were similar between the 2 arms.

In the future, how might SHR-1701 influence clinical practice for patients with gastric or GEJ cancer?

In China, Europe, and the United States, CAPOX or FOLFOX [leucovorin calcium, fluorouracil, and oxaliplatin] plus pembrolizumab [Keytruda], another anti–PD-1 antibody, is [the standard] first-line treatment for gastric cancer. Now, we have a different antibody [to combine with] CAPOX. [However, we still don’t know] the difference between PD-1 inhibitors and SHR-1701. In the future, [we may] do more clinical trials or biomarker explorations to find out which patients can benefit from SHR-1701 plus CAPOX better than a PD-1 inhibitor plus CAPOX.

In the future, we will disclose [data from this trial about] the AEs, as well as the long-term OS and PFS. We may publish [these data] in an article. There [will also be] some data we can disclose in the future. [Overall], SHR-1701 plus CAPOX is much better than chemotherapy [alone] and is also safe.

References

1. Liu D, Zhou J, Wang Y, et al. Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial. BMC Med. 2022;20(1):408. doi:10.1186/s12916-022-02605-9
2. Peng Z, Wang J, Zhang Y, et al. Phase III study of SHR-1701 versus placebo in combination with chemo as first-line (1L) therapy for HER2-negative gastric/gastroesophageal junction adenocarcinoma (G/GEJA). Ann Oncol. 2024;35(suppl_2):1-72. doi:10.1016/annonc/annonc1623