Clinical Trials Corner Issue 6(4)
In this issue, we highlight immunotherapy and antibody drug conjugate trials presented at the ESMO 2020 Virtual Conference on the management of patients with metastatic urothelial cancer. The results inform us of the combination of immunotherapy and chemotherapy, upfront immunotherapy followed by chemotherapy and combinations of immunotherapy. One trial updates the results with an ADC in patients previously treated with chemotherapy and immunotherapy. In the future, please reach out to us
... ach out to us directly in order to highlight any Study Title: Pembrolizumab alone or combined with chemotherapy versus chemotherapy alone as fi rst line therapy for advanced urothelial carcinoma (UC): Keynote 361 Clinicaltrials.gov identifi er: NCT02853305 Sponsor: Merck Sharpe and Dohme Enrollment: 1010 Rationale: The current standard for fi rst line treatment in advanced UC is cisplatin-based chemotherapy. Pembrolizumab is recommended for patients as second line therapy or as fi rst line therapy in patients that are PDL-1 positive and ineligible for platinum. Avelumab is recommended as maintenance treatment for patients who do not progress on fi rst line chemotherapy. Study Design: This was a global, randomized open label phase 3 trial comparing pembrolizumab alone or combined with platinum-based chemotherapy versus chemotherapy as fi rst line treatment for patients with locally advanced or metastatic UC. Patients were randomized 1:1:1 to pembrolizumab and chemotherapy (n=351) or pembrolizumab alone (n= 307) or chemotherapy alone (n=352). Study Title: Phase II multicenter, randomized study to evaluate effi cacy and safety of avelumab with carboplatin/ gemcitabine (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy ("INDOCUMAIN"). Clinicaltrials.gov identifi er: NCT03390595 Sponsor: Associació per a la Recerca Oncologica, Spain Enrollment: 85 Rationale: Up to 50% of patients with metastatic urothelial carcinoma (mUC) are not eligible for cisplatin. Carboplatin has activity but not comparable and so this trial evaluates whether Avelumab given as an induction therapy and in combination with carboplatin/ gemcitabine results in superior anti-tumor activity compared to standard chemotherapy in cisplatin-ineligible patients with metastatic UC. Biologically, chemotherapies can induce immunogenic cell death which may enhance the ability of checkpoint inhibitors such as avelumab. Study Design: This is a phase II multicenter, randomized trial evaluating the safety and effi cacy of the combination of avelumab plus carboplatin/ gemcitabine versus carboplatin/ gemcitabine alone in patients with metastatic UC who have not received prior systemic therapy and are cisplatin ineligible. Patients had to have an ECOG status of 0-2 and patients received 6 cycles of carboplatin/gemcitabine with or without avelumab which was given as induction (2 cycles avelumab), concurrent with chemotherapy (6 cycles), and as maintenance in the group that received it with the chemotherapy. Avelumab maintenance was continued until progression, unacceptable toxicity, or treatment discontinuation. Endpoints: The primary endpoint was overall response rate (ORR) by RECIST criteria. The secondary endpoints included PFS, OS, duration of response (DoR), and safety and tolerability. Results: The trial enrolled 42 patients in the chemoimmunotherapy arm and 42 patients in the chemotherapy alone arm. In an intention to treat analysis, the overall response rate was 57.1% versus 53.5% respectively, with no signifi cant difference between the arms. Partial and complete responses were 45.2% and 11.9% in the chemoimmunotherapy arm compared with 44.2% and 9.3% in the chemotherapy arm. Median PFS was similar at 6.9 months versus 7.4 months (p=0.1356) in the chemoimmunotherapy versus chemotherapy arms respectively. Median OS was similar at 10.5 months versus 13.2 months (p=0.2642) in the chemoimmunotherapy versus chemotherapy arms respectively. Overall, the drugs were safe and tolerable with their usual expected toxicities. Comments: Induction immunotherapy followed by chemoimmunotherapy did not signifi cantly improve outcomes in this trial. The trial is different than the fi ndings seen in the Javelin 100 study which demonstrated superior OS in the maintenance arm with avelumab. However, this initial analysis is still immature and further follow-up is needed for defi nitive conclusions.