Becotatug (JMT101), a humanized IgG1 anti-EGFR monoclonal antibody (seven-fold higher target affinity than cetuximab and two-fold higher than panitumumab), and Enlonstobart (SG001), a humanized IgG4 anti-PD-1 antibody, have both shown promising antitumor effects with good safety profiles in advanced solid tumors. 

This phase II, multicenter, randomized, open-label study investigates the safety and preliminary efficacy of combining JMT101, SG001, and irinotecan in patients with metastatic colorectal adenocarcinoma (mCRC). Eligible patients had RAS/BRAF wild-type mCRC without MSI-H/dMMR and had progressed after at least two prior systemic treatments. Following dose confirmation in a safety run-in phase, patients were randomized into three groups: 

1. JMT101 + irinotecan + SG001 (Arm A), 

2. JMT101 + irinotecan (Arm B), 

3. Regorafenib (Arm C)

The main objective is to assess objective response rate (ORR) based on RECIST v1.1 criteria. Following the safety run-in (SRI) in 3 patients, 106 more patients (median age 58 years, 62.3% male) were randomized equally across the three arms (36 in A, 35 each in B and C). By January 24, 2025, all SRI patients and 65.1% of randomized patients had completed treatment. With a median follow-up of 7.4 months, 34 patients in Arm A, 35 in Arm B, and 34 in Arm C were evaluable for efficacy. Arms A and B showed similar outcomes in ORR, DCR, and PFS, all significantly better than Arm C. 

ORR and PFS

1. Arm A: JMT101 + irinotecan + SG001 achieved ORR of 44.1%, mPFS of 5.7 months

2. Arm B: JMT101 + irinotecan achieved ORR of 34.3%, mPFS of 7.4 months

3. Arm C: Regorafenib achieved ORR of 2.9%, mPFS of 2.9 months

Duration of response (DoR)

1. Arm A: JMT101 + irinotecan + SG001 achieved mDoR of 48 months 

2. Arm B: JMT101 + irinotecan achieved mDoR of 71.4 months 

3. Arm C: Not evaluable 

Median overall survival was not yet reached. Grade ≥3 treatment-related adverse events occurred in 38.9% (Arm A), 54.3% (Arm B), and 48.6% (Arm C), with no treatment-related discontinuations in Arms A or B, compared to two in Arm C. No treatment-related deaths were reported.

KOL insights

“There are many therapeutic options for patients with mCRC, although the majority have retained their chemotherapeutic backbone. It is important to keep that in mind, as many patients express interest in pursuing immunotherapy. In reality, patients who are eligible for this approach account for less mCRC population. In terms of standard regimens, physicians can use FOLFOX or FOLFIRI. However, if a patient has a good performance status and their laboratory tests are within normal limits, it advises a more aggressive approach with FOLFOXIRI”. – Expert Opinion

“Preliminary data support continued investigation, with updated results to follow.”– Expert Opinion

Conclusion

The findings from phase II showed that JMT101 combined with irinotecan, both with and without SG001, demonstrated statistically significant superiority over regorafenib, with a pooled ORR of 39.1%, a DCR of 84.1%, and a median mPFS of 5.7 months in both EGFR-pretreated and EGFR-treatment-naive patients.

A clear advantage is seen with the JMT101/irinotecan combo for the Indication. CSPC Pharmaceutical has initiated a pivotal phase III clinical trial evaluating JMT101 in combination with irinotecan for its specified indication. Additionally, JMT101 is undergoing multiple phase II and III trials in China for the treatment of various solid tumors, including lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma, across first-line and later-line settings. With its promising efficacy and safety profile, a Breakthrough Therapy Designation recently granted  for treatment of colorectal cancer by China's National Medical Products Administration (NMPA) which is expected to further expedite its research and development process.