(UroToday.com) The 2023 GU ASCO annual meeting included an oral abstract session on urothelial carcinoma, featuring a discussant presentation by Dr. Andrea Apolo discussing two abstracts: “Atezolizumab + platinum/gemcitabine vs placebo + platinum/gemcitabine for first-line treatment of locally advanced or metastatic urothelial carcinoma: Final OS from the randomized Phase 3 IMvigor130 study” presented by Dr. Enrique Grande and “Final OS analysis of atezolizumab monotherapy vs chemotherapy in untreated locally advanced or metastatic urothelial carcinoma from the Phase 3 IMvigor130 study” presented by Dr. Aristotelis Bamias. Dr. Apolo notes that unfortunately both of these trials were negative, but what have we learned?
Among cisplatin-eligible patients, cisplatin + gemcitabine has a median overall survival of 13.8 months, and among cisplatin-ineligible patients (as defined by the Galsky criteria determining patients to be unfit for cisplatin – ECOG >=2, CrCl < 60 mL/min, Grade >=2 hearing loss, Grade >= 2 neuropathy, NY Heart Association Class III heart failure), carboplatin + gemcitabine has a median overall survival of 9.3 months. In 2016-2017, the FDA listed five second-line approvals:
- Atezolizumab (May 2016)
- Nivolumab (February 2017)
- Durvalumab (May 2017)
- Avelumab (May 2017)
- Pembrolizumab (May 2017)
Dr. Apolo wonders, if it works in other solid tumors, will combination chemotherapy + checkpoint inhibitors in the first line setting work in metastatic urothelial carcinoma? Indeed, there are FDA approvals of chemotherapy + checkpoint inhibitor immunotherapy in: non-small cell lung cancer, small cell lung cancer, squamous small cell lung cancer, triple-negative breast cancer, head and neck cancer, cervical cancer, and gastric cancer/gastroesophageal junction cancer. Looking at metastatic urothelial carcinoma, we have 4 trials: IMvigor130 (positive for PFS at ESMO 2019), KEYNOTE-361 (negative at ESMO 2020), NILE (awaiting data), and CheckMate-901 (negative in the PD-L1+ population, press release May 2022):
Dr. Apolo then discussed the abstract by Grande et al. At ESMO 2019, the primary analysis demonstrated a significant rPFS benefit for Arm A vs Arm C, with OS presented as an interim analysis showing promise, but not reaching statistical significance. In the final OS analysis, as of the data cutoff of August 31, 2022 (49 months since the last patient was randomly assigned), in ITT patients, OS benefit was not statistically significant in the cisplatin subgroup (HR 0.85, 95% CI 0.73, 1.00):
Does chemotherapy combine better with PD-1 or PD-L1? When looking at Arm A of IMvigor130 (median overall survival 16.1 months), the results are very similar to pembrolizumab + chemotherapy (median overall survival 17.0 months) in KEYNOTE-361:
Atezolizumab was given until progressive disease (median treatment duration of 6 months in Arm A), and pembrolizumab was given for a maximum of 35 cycles (median treatment of 7.7 months). Dr. Apolo notes that it is difficult to compare the IMvigor130 (combination treatment in all first line patients) population with the JAVELIN Bladder 100 study population (only responders to first line chemotherapy received avelumab) as these are different patient populations. However, the length of checkpoint inhibitor therapy was similar in both trials (~6 months in both).
Does cisplatin combine better than carboplatin with checkpoint inhibitors? When looking at OS by choice of platinum chemotherapy, there was no benefit whether patients received cisplatin (HR 0.76, 95% CI 0.57, 1.01) or carboplatin (HR 0.89, 95% CI 0.74, 1.08):
Interestingly, because it was the investigator’s choice of cisplatin versus carboplatin, many patients were eligible for cisplatin (~75%), but only a fraction received it (~30-34%). Furthermore, although there was some benefit to cisplatin vs carboplatin in IMvigor130, there was no difference in the KEYNOTE-361 trial. We are currently awaiting data on cisplatin-based combination from CheckMate-901 and ongoing neoadjuvant trials in muscle invasive bladder cancer:
Next, Dr. Apolo discussed the abstract from Bamias et al. The atezolizumab monotherapy arm in IMvigor130 is comparable to the pembrolizumab monotherapy arm in KEYNOTE-361, the durvalumab monotherapy arm in DANUBE, and nivolumab + ipilimumab in CheckMate-901:
OS data for this analysis in IMvigor130 did not show benefit for ITT patients for Arm B vs Arm C (HR 0.98, 95% CI 0.82, 1.16):
Importantly, this is in line with the other monotherapy checkpoint inhibitor versus platinum-based chemotherapy trials:
However, unlike the other trials, there was an OS benefit in PD-L1 patients for atezolizumab monotherapy in IMvigor130:
Dr. Apolo then highlighted first line cisplatin-ineligible accelerated approvals in metastatic urothelial carcinoma. This included atezolizumab (accelerated approval April 2017) and pembrolizumab (accelerated approval May 2017). The FDA’s Accelerated Approval Program allows for earlier approval of drugs that treat severe conditions and fill a medial need based on a surrogate endpoint. As of April 2021, the FDA held an ODAC meeting to discuss the first line accelerated approval of atezolizumab and pembrolizumab in metastatic urothelial carcinoma, with the atezolizumab-ODAC voting 10 to 1 in favor of keeping the indication. in August 2021, the FDA removed the first line indication for pembrolizumab in cisplatin-ineligible PD-L1 high metastatic urothelial carcinoma but continued approval for platinum-ineligible patients. In November 2022, atezolizumab was voluntarily withdrawn from its first-line indication in metastatic urothelial carcinoma. As such, the monotherapy indications for checkpoint-inhibitors in metastatic urothelial carcinoma is for avelumab as maintenance after response to first line chemotherapy. Including second line therapy and beyond, as follows is the current systemic treatment landscape for metastatic urothelial carcinoma:
Will platinum-based chemotherapy become second-line treatment? Dr. Apolo then discussed the antibody drug combination of enfortumab vedotin + pembrolizumab. The EV-103 Cohort K tested enfortumab vedotin + pembrolizumab in first line cisplatin ineligible metastatic urothelial carcinoma, with an objective response rate of 64.5%. EV-302 is testing enfortumab vedotin + pembrolizumab versus chemotherapy in the phase 3 setting, which is fully accrued and still awaiting data. Finally, EV-304 is testing enfortumab vedotin + pembrolizumab versus chemotherapy in cisplatin-eligible muscle invasive bladder cancer in the neoadjuvant setting. In December 2022, the FDA accepted an application for priority review for the accelerated approval of enfortumab vedotin + pembrolizumab for the first line treatment of cisplatin-ineligible patients with metastatic urothelial carcinoma.
Dr. Apolo concluded her discussant presentation with the following take-home messages:
- Chemotherapy + checkpoint inhibitor combinations have different efficacy in a variety of solid tumors
- The combination of chemotherapy + checkpoint inhibitors did not work with atezolizumab (PD-L1 inhibitor) or with pembrolizumab (PD-1 inhibitor)
- The chemotherapy used in the chemotherapy + checkpoint inhibitor combinations may make a difference. Cisplatin may be a better choice; additional data from other trials are pending
- Hierarchal studies limit the statistical testing of subsequent study arms if the first questions asked are negative
- Monotherapy checkpoint inhibitor is no longer an FDA-approved standard of care option for first line treatment of platinum-eligible patients
- Ongoing trials are assessing the efficacy of antibody drug conjugates + checkpoint inhibitors versus chemotherapy in the metastatic and neoadjuvant setting
Presented by: Andrea B. Apolo, MD, National Cancer Institute, Bethesda, MD
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.
Related Content:
Long-Term Results of the IMvigor130 Study: Atezolizumab with or without Chemotherapy in Metastatic Urothelial Cancer – Matthew Galsky