The ESMO 2021 annual congress kick started itself with the unveiling of updated findings by pharma giants, namely Roche, Daiichi Sankyo, Mirati Therapeutics, Merck, BMS, Coherus BioSciences, Bayer, and others in different oncology indications, including GI cancers. The big Chinese biopharmaceuticals such as Innovent Biologics, Shanghai Junshi Biosciences, and BeiGene also strived harder to present their key findings from their late phase clinical trials at the meeting.
Among the major abstracts published during the virtual conference, Innovent biologics grabbed the opportunity to exhibit outstanding results from the ongoing ORIENT-16 trial and ORIENT-15 trial. The drug under investigation – sintilimab is a PD-1 inhibitor developed by Innovent in collaboration with Eli Lilly. It is approved in China with the brand name Tyvyt to treat patients with Hodgkin lymphoma, NSCLC, or hepatocellular carcinoma. Additionally, in May 2021, the US FDA accepted for review the BLA for sintilimab in combination with pemetrexed and platinum chemotherapy in first line NSCLC.
ORIENT-16: Innovent biologics is investigating Sintilimab as first line of therapy (LOT) for patients with unresectable or metastatic gastric or gastroesophageal adenocarcinoma exclusively in China in a phase III trial in combination with the chemotherapy agents. The drug demonstrated improvement in OS compared with chemotherapy alone, reaching the predefined primary endpoint. It has been reported that at the median follow-up of 18.8 months, the median OS was 15.2 months in the experimental arm versus 12.3 months in the chemotherapy arm. In the CPS ≥ 5 population, the median OS was 18.4 months in the experimental arm versus 12.9 months in the control arm. PFS was superior with sintilimab in the total population (7.1 versus 5.7 months) and the CPS ≥ 5 population (7.7 versus 5.8 months). In all patients with measurable disease, the ORR was 58.2% versus 48.4% in favor of sintilimab, with a median DOR of 9.8 months and 7.0 months, respectively. In the PD–L1-positive population, the unconfirmed ORR was 72.8% in the experimental arm versus 59.6% in the chemotherapy arm. Overall, 59.8% of patients in the experimental arm and 52.5% in the chemotherapy arm experienced grade ≥ 3 TRAEs. Based on the published results, we remain buoyant about the drug’s entry into the market. However, considering the safety issues, the immunotherapeutic agent, sintilimab demonstrated a comparable safety profile in comparison to the chemotherapeutic agent.
ORIENT-15: The company also presented promising safety and efficacy results from another phase III trial, ORIENT-15, which evaluated frontline sintilimab along with chemotherapy in esophageal squamous cell carcinoma (ESCC). The results demonstrated that median OS favored the experimental arm in all patients at 16.7 months versus 12.5 months in the control arm. In patients with a PD-L1 CPS of ≥ 10, the median OS again favored the combination arm at 17.2 months versus 13.6 months in the patient chemotherapy arm. Similarly, median PFS was superior in all patients (7.2 months versus 5.7 months) and those who were PD-L1–positive (8.3 months versus 6.4 months). The ORR was 66.1% in favor of sintilimab/chemotherapy in the overall population, while it was 78.7% versus 57.5% in CPS ≥ 10 patients. Grade 3 or greater TRAE rates were 59.9% in the sintilimab/chemotherapy. The results demonstrated that the combination can be considered as a new standard of care in the first LOT in patients with advanced or metastatic ESCC.
Expert opinion: “First results from the phase III ORIENT-15 trial in ESCC and the phase II ORIENT-16 clinical trial in GEJ showed that sintilimab was well tolerated in both groups of patients. Additionally, sintilimab improved survival in patients with ESCC across all subgroups. The combination showed significant OS benefits versus chemo alone in patients with advanced or metastatic ESSC, regardless of PD-L1 expression level. Consistent benefits were observed in prespecified groups. PFS and the DOR are significantly improved.”
– Expert Opinion
JUPITER-06: Apart from much-awaited and exciting results from Innovent Biosciences, we cannot overlook the Phase III results demonstrated by Coherus and Junshi Biosciences from JUPITER-06 trial, evaluating Toripalimab in combination with chemotherapy as first-line treatment for advanced ESCC. The drug under investigation was the first domestic anti-PD-1 monoclonal antibody approved for marketing in China as Tuoyi. Additionally, the drug has been granted conditional approval from the NMPA for the second-line treatment of unresectable or metastatic melanoma, recurrent or metastatic nasopharyngeal carcinoma after failure of at least two LOT, and locally advanced or metastatic urothelial carcinoma who failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. In addition, two sNDAs for toripalimab in combination with chemotherapy for the first-LOT for patients with advanced, recurrent, or metastatic NPC or first-LOT for patients with advanced, or metastatic ESCC were accepted by the NMPA for review in February and July 2021 respectively.
The results presented on the second day of the ESMO 2021 reported that after a median follow-up of 7.3-7.4 months, the research team observed a significant improvement in the median OS in the toripalimab arm (17 months) compared with the placebo arm (11 months). The 1-year OS rate in the toripalimab arm was 66.0% compared with 43.7% in the placebo arm. The median PFS was 5.7 months for the toripalimab arm compared with 5.5 months for the placebo arm. The 1-year PFS rate was 27.8% for the toripalimab arm compared with 6.1% for the placebo arm. Among patients with PD-L1 expression with a CPS ≥ 1, the median OS in the toripalimab arm was 15.2 months compared with 10.9 months in the placebo arm. In patients with CPS < 1, the median OS was not reached compared with 11.6 months in the placebo arm. Moreover, grade 3 or worse AEs occurred at nearly similar rates in both arms and the incidence of serious AEs was also similar.
Based on the findings, we believe that the use of toripalimab with chemotherapy could provide clinical benefits as first-LOT for patients with ESCC. The findings of this interim analysis provide strong evidence that the addition of toripalimab to chemotherapy as a first-line treatment for advanced or metastatic ESCC patients has superior PFS and OS than chemotherapy alone. We believe toripalimab could be a potential new treatment choice where patients truly need better options. Moreover, the companies are planning to submit a BLA supplement for 1L ESCC in 2022.
“Toripalimab in combination with paclitaxel and cisplatin has the potential to become a new standard first-line therapy in patients with advanced or metastatic ESCC. Overall, these results support the use of toripalimab with chemotherapy as a new first-line treatment for advanced or metastatic ESCC.”
– Expert Opinion
INSIGHTS: Immunotherapy has immensely changed the treatment paradigm for various malignancies, but it still needs to be studied in gastric cancer. The treatment options for advanced gastric cancer are very limited including the recently approved BMS’ nivolumab (Opdivo) in combination with chemotherapy as well as Merck’s all-rounder, pembrolizumab (Keytruda) in combination with trastuzumab and chemotherapy (HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma). Delveinsight believes that the results from the ORIENT-16 study might bring a new ray of hope in patients with treatment naïve metastatic gastric cancer in terms in of survival benefits and also anticipates good fortune for the Chinese biopharma in the global market. Let us now wait and watch how sintilimab would compete with already established key players in the market and what efficacy it would show in an area where the advanced stage appears to overpower the immunotherapy.
Moreover, Sintilimab and Toripalimab demonstrated similar mOS values in their respective clinical trials. Based on the current findings presented by Innovent and Coherus, we believe that the results for both drugs are comparable. The already established key players like pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy (Keynote-590) and nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy (Checkmate-649) have been recently approved this year for the first-line disease. It would be now interesting to watch how the Chinese biopharma candidates would tussle with the already approved therapies in the market. Owing to this scenario, Delveinsight is quite optimistic with the recent data readouts from the ORIENT-15 and JUPITER-06 trials and predicts that, if approved, these therapies might take a significant share in the global market for the indication.
*Renal cell carcinoma (RCC), Objective response rate (ORR), complete response (CR), Non-small cell lung cancer (NSCLC), Triple-negative breast cancer (TNBC), Partial response (PR), Dose-limiting toxicities (DLT), Combined Positive Score (CPS)