- If patients were eligible for cisplatin chemotherapy - gemcitabine/cisplatin (median overall survival (OS) 12-14 months)
- If patients were ineligible for cisplatin chemotherapy - gemcitabine/carboplatin (median OS 8-12 months)
- If the patients had platinum-refractory disease - taxane or vinflunine (median OS 6-8 months)
As of July 2018, the treatment algorithm is as follows:
- If patients were eligible for cisplatin chemotherapy - gemcitabine/cisplatin (median OS 8-12 months)
- If patients were ineligible for cisplatin chemotherapy, PD-L1 positive - atezolizumab (median OS 12.3 months1) or pembrolizumab (median OS 18.5 months2)
- If patients were ineligible for cisplatin chemotherapy, PD-L1 negative - gemcitabine/carboplatin (median OS 8-12 months)
The IMvigor130 data showed us that the final progression-free survival (PFS) for atezolizumab + platinum chemotherapy/gemcitabine vs placebo + platinum chemotherapy/gemcitabine favored the atezolizumab combination arm (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.70-0.96). However, Dr. Powles notes that currently this combination has not quite demonstrated an OS benefit (HR 0.83, 95% CI 0.69-1.00). Furthermore, looking at the subgroup analyses, atezolizumab + platinum chemotherapy/gemcitabine does not improve PFS in the PD-L1 negative patients: ICS0, HR 0.79, 95% CI 0.61-1.03; ICS2/3 HR 0.89, 95% CI 0.70-1.13.
So, do these results for combination therapy change the algorithm proposed above as of July 2018?
- Significant delay in PFS
- OS trending the right way
- Complete response rate of 13% (vs 7%)
- No increase in adverse events for the combination therapy
- PFS HR 0.82, 95% CI 0.70-0.96
- OS is not significant, yet
- Response rates of 47% (vs 44%)
- There is no quality of life/patient-reported outcomes data
In Dr. Powles' opinion, we probably need to wait for the overall survival data from the combination arm before changing the treatment paradigm. Do the results of the monotherapy arm change clinical practice? The OS data versus placebo + platinum chemotherapy/gemcitabine show an encouraging OS with a HR of 0.68 (95% CI 0.43-1.08). However, only 24% of the population was biomarker positive with a response rate of 23% vs 44%. Importantly, there is no subset analysis of the cisplatin population, so in Dr. Powles' opinion, the paradigm does not change yet. This strengthens the case for using atezolizumab in PD-L1 positive patients in platinum ineligible patients, but not in the cisplatin eligible patients yet.
Dr. Powles concluded this discussion of IMvigor130 with several summary statements:
- This is the first positive trial in this setting and underpins the activity of atezolizumab in urothelial carcinoma
- The combination arm is statistically significant but not yet clinically transformative without OS benefit
- The monotherapy arm is clinically meaningful but not statistically robust enough yet
- More detail on the trial design and subset populations is also needed
- This and other trials may be clinically transformative in the future
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct, 2019 in Barcelona, Spain
- Balar, Arjun V., Matthew D. Galsky, Jonathan E. Rosenberg, Thomas Powles, Daniel P. Petrylak, Joaquim Bellmunt, Yohann Loriot et al. "Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial." The Lancet 389, no. 10064 (2017): 67-76.
- Balar, Arjun V., Daniel Castellano, Peter H. O'Donnell, Petros Grivas, Jacqueline Vuky, Thomas Powles, Elizabeth R. Plimack et al. "First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study." The Lancet Oncology 18, no. 11 (2017): 1483-1492.