Discussion
cancers, neuropathy, toxicity, toxicities, ’, tumour, adenocarcinoma, gastric cancer
SOLID TUMOUR, CANCERS, NEUROPATHY, GASTROESOPHAGEAL CANCER, METASTATIC GASTRIC CANCER, TUMOUR, ADENOCARCINOMA, GASTRIC CANCER
The treatment landscape for metastatic gastric and GEJ adenocarcinoma has changed significantly over the past several years with the approval of immunotherapy in combination with 5-fluorouracil and platinum as initial treatment. After progression on initial therapy, approved second-line regimens are ramucirumab as monotherapy or in combination with paclitaxel. However, neuropathy from first-line treatment may complicate the use of paclitaxel as second-line treatment. Aside from ramucirumab monotherapy, there are no available second-line treatment options for gastric and GEJ adenocarcinoma that might spare patients from the toxicities of cytotoxic chemotherapy. Thus, the development of novel targeted treatment options remains an unmet need for gastric and GEJ adenocarcinoma. Here we report the results for the first study evaluating a PARP inhibitor in combination with a VEGFR2-targeted antibody in any solid tumour.In the Phase 1 dose escalation, there were no unexpected safety signals, and the RP2D was the protocol-specified highest dose: olaparib 300 mg twice daily with ramucirumab 8 mg/kg on day 1 in 14-day cycles, which is consistent with the full dose monotherapy dose intensity for both agents. In dose expansion, 40 additional patients were enroled at the RP2D. The ORR for all enrolled patients at the RP2D evaluable for response by RECIST was 6/43 (14%), and in the intention-to-treat population the median PFS and median OS were 2.8 months and 7.3 months, respectively. These efficacy results compare favourably to ramucirumab monotherapy as the second-line Phase 3 REGARD clinical trial had a ORR of 3%, median PFS 2.1 months and median OS 5.2 months [The genomic analysis was available for 35 patients (10 WES and 25 BROCA-HR). Eleven cancers were determined to be HRD-positive due to the presence at least one mutation in the 17 HRD genes that were pre-specified to confer PARP inhibitor sensitivity as outlined in the methods. This included 4 The NCI10066 study is limited due to the sample size and lack of randomisation which makes it difficult to generalise these findings to all patients with gastric cancer. The patient heterogeneity in regard to number of prior treatments also complicates the interpretation of the efficacy endpoints, and may ultimately result in an underestimation of the ORR and survival of the combination. While the genomic results are available for many patients, given the mechanism of olaparib, a more comprehensive genomic analysis of the study population would strengthen the conclusion that the olaparib and ramucirumab combination works regardless of HRD. Furthermore, while our definition of HRD for data analysis was determined at the time of study development, a more modern definition of HRD genes and functional HRD scores that also accounts for platinum sensitivity would be more appropriate for a future clinical trial. Ultimately a randomised study in a more uniform patient population will be needed to make more definitive measurements for the efficacy of the treatment combination. Other future development strategies for olaparib and ramucirumab may be in combination with immune checkpoint inhibitors given the immunogenicity of gastroesophageal cancer, non-overlapping toxicity profiles, and potential for synergy in preclinical models [In conclusion, the NCI10066 trial confirmed the safety of olaparib 300 mg twice daily with ramucirumab 8 mg/kg on day 1 in 14-day cycles. The ORR, PFS, and OS with olaparib and ramucirumab are all superior compared to the historical control of ramucirumab monotherapy for metastatic gastric cancer. Future clinical trials could include ramucirumab and olaparib compared to ramucirumab monotherapy as a chemotherapy-free approach for patients’ ineligible for cytotoxic chemotherapy. In NCI10066, we observed anti-tumour activity for patients with and without tumour HRD, which suggests the combination of ramucirumab and olaparib may be superior to ramucirumab monotherapy and a randomised trial is warranted for gastric cancer in the second-line treatment setting.