Discussion
NSCLC, SCLC, tumor, esophageal cancer, melanoma, multiple cancer, HCC, biliary tract carcinoma, breast cancer, cancer, malignancies
TUMOR, SCLC, MULTIPLE CANCER, MELANOMA, CANCER, SOLID TUMORS, MALIGNANCIES, CERVICAL CANCER, NSCLC, CPS, NEUROENDOCRINE TUMORS, KIDNEY CANCER, GASTRIC CANCER
To the best of our knowledge, this is the first phase I clinical trial of a bifunctional MabPair product providing dual inhibition of PD-1 and CTLA-4 (QL1706), and it is the largest phase I trial of a dual immune checkpoints inhibitor. QL1706 was well tolerated, with only 83 out of 518 (16%) participants experiencing TRAEs of grade ≥ 3. In addition, it exhibited good antitumor activity in multiple cancer types including NSCLC, NPC, CC, and SCLC, especially in heavily pretreated immune-naive NPC and cervical cancer patients, with ORRs of 38.7% and 28.3% and the DoR not researched in the median follow-up time of 10.9 (95% CI 10.7–11.4) and 7.5 (95% CI 7.2–8.2) months, respectively.In contrast to a bispecific antibody (i.e., KN046 and cadonilimab) that covers the two targets of PD-1 and CTLA-4 equally [As shown in this study, QL1706 is generally well tolerated, and TRAEs of grade ≥ 3 occurred in 16.0% of the patients. Previous studies have shown that the pooled incidence of TRAEs of grade ≥ 3 with the combination treatment of nivolumab and ipilimumab in advanced malignancies was 39.9% [The efficacy of QL1706 in patients with diverse tumor types was investigated in 468 patients, and 16.9% (79/ 468) had objective responses with durability. ORRs of 12.5–33% were observed in NSCLC, NPC, CC, SCLC, kidney cancer, melanoma, and neuroendocrine tumors. Based on the preliminary results, the efficacy of QL1706 in these tumor types deserved further evaluation. QL1706 demonstrated limited efficacy in CRC, HCC, biliary tract carcinoma, breast cancer, esophageal cancer, and gastric cancer. Though no conclusion can be drawn with such a small sample size, the mechanisms of poor efficacy need to be explored to guide further drug development.In immunotherapy-naive NPC patients, the ORR of QL1706 was 38.7%, and the mDoR was NR (> 7.7 months). The ORR was relatively greater than that of other PD-1 antibodies, like nivolumab (ORR: 20.5%) [At present, there are limited treatment options for patients with advanced CC and SCLC, especially for pretreated ones. A phase II study of pembrolizumab for patients with pretreated advanced cervical cancer achieved an ORR of 12.2% [In the present study, the promising efficacy of QL1706 may be independent of the expression of PD-1, since patients with CPS < 1 also showed a relatively high response. However, due to the small sample size, further clinical trials with a larger sample size are needed to confirm this hypothesis.This study has some limitations that must be addressed, including the absence of randomization in phase Ib and the lack of quality-of-life outcome evaluations in our analyses. Moreover, only Chinese patients were enrolled. The efficacy of QL1706 on other ethnic populations warrants further trials.In conclusion, QL1706, the first-in-class bifunctional MabPair product with dual blockade of PD-1 and CTLA-4 showed a good safety profile and encouraging antitumor activity in this large-sample phase I study of advanced solid tumors. It is a potential new option for cancer dual immunotherapy and a backbone agent for combined therapy, which needs to be further developed.