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Is Chemoimmunotherapy Prime Time for First-Line Metastatic Urothelial Carcinoma?

Results from a first-line chemoimmunotherapy trial in patients with metastatic urothelial carcinoma were recently presented at the 2019 European Society of Medical Oncology (ESMO) Congress.1 These early results from the IMvigor 130 trial provide the first hints that novel combination therapy offers benefit for patients with locally advanced or metastatic urothelial carcinoma. This trial randomized patients to atezolizumab plus platinum/gemcitabine (Arm A) vs. atezolizumab monotherapy (Arm B) vs. placebo plus platinum/gemcitabine (Arm C).

The platinum agent could either be cisplatin or carboplatin and was selected by the investigator for the patient. The final progression-free survival (PFS) in the intention to treat the population of Arm A vs. Arm C was statistically significant with a stratified hazard ratio (HR) 0.82 (95% confidence interval (CI) 0.70-0.96); p=0.007. Median PFS was 8.2 months for Arm A with chemoimmunotherapy compared with 6.3 months with Arm C chemotherapy with placebo. However, overall survival was not statistically significant with a stratified HR 0.83 (95% CI 0.69-1.00); p=0.027. The statistical design mandated an alpha of 0.025 or better to reach statistical significance. There was no obvious improvement in objective response rate between chemoimmunotherapy versus chemotherapy with placebo, as confirmed response rates were 47%, 23% and 44% for Arm A, B and C, respectively. The safety summary was as expected for the independent agents without clear potentiation of any chemotherapy-associated toxicities or immune-mediated toxicities in the combination therapy arm.

At this point in time, the combination of chemoimmunotherapy is not regulatory approved. Our current treatment algorithm should likely not change at this time, given the significant delay in PFS, yet only trend for overall survival. Mature overall survival data would obviously help to institute up-front chemoimmunotherapy into our clinical practices. 

While we wait for the overall survival data to mature from IMvigor 130 and results from a similar trial with pembrolizumab (KEYNOTE 361), we should pay special attention to the numerous combination trials that are actively accruing patients. There are multiple regulatory approved PD-1/PD-L1 antibodies, that include atezolizumab, nivolumab, durvalumab and avelumab, approved for their response rate in patients with metastatic disease in the post-platinum chemotherapy setting.2-5 Pembrolizumab is also regulatory approved and is the only agent to have demonstrated an overall survival benefit to date when compared to taxane chemotherapy in the post-platinum setting.6 Additionally, atezolizumab and pembrolizumab are approved for patients who are ineligible for cisplatin chemotherapy in the 1st-line metastatic disease setting.7,8 All of these agents are being actively combined with other novel therapeutics in various advanced disease settings, and completing accrual to these trials will benefit our patients and the field immensely. 

Even if combination therapy, e.g. chemoimmunotherapy, is demonstrated to be definitively efficacious with front-line administration for patients with metastatic urothelial carcinoma, the opportunity still currently exists to gather more knowledge about rationale biologic combinations. This knowledge will be useful to design better treatment paradigms and also to elucidate mechanisms of resistance and methods to abrogate those mechanisms. Hence, we should aggressively accrue to the open trials, highlighted below, with strong hope that the results will further expand treatment options for our patients.   

Clinical Trials of Combination PD-1/PD-L1 Therapy with Novel Agents for Urothelial Bladder Carcinoma:

  • Derazantinib and Atezolizumab (NCT04045613)
  • CYT107 and Atezolizumab (NCT03513952)
  • Rogaratinib and Atezolizumab (NCT03473756)
  • Bevacizumab and Atezolizumab (NCT03272217)
  • Guadecitabine and Atezolizumab (NCT03179943)
  • Cabozantinib and Atezolizumab (NCT03170960)
  • Pemigatinib and Pembrolizumab (NCT04003610)
  • LN-145 and Pembrolizumab (NCT03935347)
  • Lenvatinib and Pembrolizumab (NCT03898180)
  • Tazemetostat and Pembrolizumab (NCT03854474)
  • Cabozantinib and Pembrolizumab (NCT03534804)
  • Neutron radiation therapy and Pembrolizumab (NCT03486197)
  • Nab Paclitaxel and Pembrolizumab (NCT03464734)
  • SBRT and Pembrolizumab (NCT03287050)
  • sEphB4-HAS and Pembrolizumab (NCT02717156)
  • Vorinostat and Pembrolizumab (NCT02619253)
  • Ibrutinib and Pembrolizumab (NCT02599324)
  • Paclitaxel and Pembrolizumab (NCT02581982)
  • Docetaxel or Gemcitabine and Pembrolizumab (NCT02437370)
  • IPI-549 and Nivolumab (NCT03980041)
  • Bempegaldesleukin (NKTR-214) and Nivolumab (NCT03785925)
  • Sitravatinib and Nivolumab (NCT03606174)
  • Trastuzumab Deruxtecan (DS-8201a) and Nivolumab (NCT03523572)
  • Bempegaldesleukin (NKTR-214) and Nivolumab +/- Ipilumumab (NCT02983045)
  • Cabozantinib S-malate and Nivolumab (NCT02496208)
  • Vactosertib and Durvalumab (NCT04064190)
  • Radiation and Durvaluamb +/- Tremelimumab (NCT03601455)
  • AVB-S6-500 and Avelumab (NCT04004442)
  • Pemetrexed and Avelumab (NCT03744793)
  • Taxane and Avelumab (NCT035750130)
Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References:

  1. Rosenberg, Jonathan E., Jean Hoffman-Censits, Tom Powles, Michiel S. Van Der Heijden, Arjun V. Balar, Andrea Necchi, Nancy Dawson et al. "Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial." The Lancet 387, no. 10031 (2016): 1909-1920.
  2. Sharma, Padmanee, Margitta Retz, Arlene Siefker-Radtke, Ari Baron, Andrea Necchi, Jens Bedke, Elizabeth R. Plimack et al. "Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial." The Lancet Oncology 18, no. 3 (2017): 312-322.
  3. Massard, Christophe, Michael S. Gordon, Sunil Sharma, Saeed Rafii, Zev A. Wainberg, Jason Luke, Tyler J. Curiel et al. "Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer." Journal of Clinical Oncology 34, no. 26 (2016): 3119.
  4. Apolo, Andrea B., Jeffrey R. Infante, Omid Hamid, Manish R. Patel, Ding Wang, Karen Kelly, Anthony E. Mega et al. "Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: Analysis of safety, clinical activity, and PD-L1 expression." (2016): 4514-4514.
  5. Bellmunt, Joaquim, Ronald De Wit, David J. Vaughn, Yves Fradet, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang et al. "Pembrolizumab as second-line therapy for advanced urothelial carcinoma." New England Journal of Medicine 376, no. 11 (2017): 1015-1026.
  6. 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.
  7. 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.