The Uromigos Episode 161: Platinum Ineligibility in Urothelial Cancer

Although cisplatin-based combination chemotherapy is still considered first-line standard of care in metastatic urothelial carcinoma (mUC), many patients are deemed ineligible for treatment with cisplatin. The first ineligibility criteria for cisplatin were set out by Galsky et al in 2011 as Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2; creatinine clearance (CrCl), (calculated or measured) <60 mL/min; grade ≥2 hearing loss; grade ≥2 neuropathy, and/or New York Heart Association (NYHA) Class 3 heart failure.¹

However, no consensus has been reached on cisplatin ineligibility or eligibility criteria for patients with mUC, and current treatment guidelines vary in their definitions, where they are specified.^2-4 As a result, it is widely believed that cisplatin is being underused and that using a cutoff of CrCl <60 mL/min excludes many patients who might benefit from neoadjuvant cisplatin-based therapy but who are offered alternative, inferior regimens. Accordingly, there have been calls for a standardized definition of the cisplatin ineligibility in this patient population.^5,6

Defining Cisplatin Ineligibility

Shilpa Gupta, MD, Director of the Genitourinary Medical Oncology at Taussig Cancer Institute and Co-leader of the Genitourinary Oncology Program at Cleveland Clinic, Ohio, has been prominent in working toward a standardized definition of cisplatin ineligibility and co-authored a new algorithm for determining cisplatin eligibility for neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer (MIBC).⁶ In a recent discussion with Thomas Powles, MBBS, MD (Barts Cancer Centre, London, UK) and Brian Rini, MD (Vanderbilt University, Nashville, TN), Dr Gupta explained her approach to platinum ineligibility in her own practice.

In the real world, Dr Gupta maintained, physicians are very comfortable using cisplatin in patients with CrCl 50-60 mL/min, with split-dose cisplatin often used. “I think from a more practical point of view, CrCl <50 mL/min is a better accepted definition, and this is being increasingly used in clinical trials nowadays,” she noted. “For the most part, the population of platinum-ineligible patients is not very high in my practice,” she added.

Dr Gupta recalled that the need to define cisplatin ineligibility was highlighted in 2018 when the Food and Drug Administration (FDA) restricted the use of pembrolizumab and atezolizumab in cisplatin-ineligible patients with locally advanced or metastatic UC to those with high PD-L1-expressing tumors or those ineligible for any platinum therapy, regardless of PF-L1 status.⁷ The FDA’s decision was based on clinical trial data showing that patients with PD-L1 low status on monotherapy with either of these drugs have decreased survival compared with patients on cisplatin- or carboplatin-based chemotherapy. However, the FDA provided no definitions of cisplatin or platinum ineligibility, which were left to the clinician’s discretion.

Physician Survey on Cisplatin

Following the FDA’s decision, Dr Gupta and colleagues conducted a survey of US medical oncologists to determine what criteria they would use to define platinum (cisplatin and carboplatin) ineligible mUC.⁸ Based on the views of the respondents, Dr Gupta’s group recommended a definition based on one of five parameters: ECOG PS >3; CrCl <30 mL/min; peripheral neuropathy grade >3; NYHA Class >3 heart failure; or ECOG PS2 and CrCl <30 mL/min.

Among the survey respondents, there was little support for age as a criterion for cisplatin ineligibility, but about 50% support for hearing loss. Dr Powles was concerned that many older patients with hearing aids would face further loss with cisplatin. Dr Gupta believes that a patient with metastatic disease and a hearing aid, who is willing to take the risk, should be deemed eligible for cisplatin-based therapy. “I caution the patient that hearing loss can worsen, but that cisplatin is a curative treatment in the neoadjuvant setting, and most patients are willing to take that risk and be monitored closely, stopping if it worsens,” she said. “For the metastatic disease, I am OK with giving carboplatin to these patients,” she added, “but I tend to discuss with patients the nature of cisplatin and how it’s preferable over carboplatin in the neoadjuvant setting.”

Dr Rini stated that he is unwilling to give cisplatin to a patient with a hearing aid and risk further hearing loss, and Dr Powles cautioned that “in the neoadjuvant setting, many patients don’t need chemotherapy at all. Although it’s curative, the benefits are relatively modest, and one is in danger of putting patients into a lifetime of hearing damage.” Dr Gupta agreed, but stressed that if patients have no other comorbidities deeming them ineligible for cisplatin, then they can be monitored closely for hearing loss “But if a patient has ECOG PS 2, CrCl 50 mL/min, and hearing loss, then they absolutely don’t qualify for any chemotherapy,” she noted.

Dr Powles recalled that the FDA has described the cisplatin-ineligible population as an area of unmet need. “Because of that, it was possible to get accelerated approvals and that resulted in looking at that population almost exclusively in our trials,” he noted. “The DANUBE,⁹ KEYNOTE-361¹⁰ and IMvigor30¹¹ trials showed the outcomes for cisplatin and the carboplatin patients are almost identical,” he said. “I would say that both populations are unmet needs and there are more similarities than differences in their outcomes.”

Other Studies and Trials

Dr Gupta pointed out that 2 years ago, the results of the JAVELIN Bladder 100¹² showed that gemcitabine plus carboplatin was ‘back in the game,’ followed by avelumab maintenance in patients who do not progress. “Even without the maintenance arm, those patients did better initially than with single agent immunotherapy,” she noted. “So we are back to the era of using carboplatin in these patients, followed by switch maintenance approaches. I think we have gone too much into cisplatin eligibility and defining anybody as platinum-ineligible to get non carboplatin-based treatments,” she said.

Dr Powles pointed out that this discussion might be less relevant in a few years’ time, after release of the results of the: EV-302 (NCT04223856) phase 3 study of enfortumab vedotin plus pembrolizumab versus chemotherapy in previously untreated advanced UC. “There is a good chance that enfortumab vedotin plus pembrolizumab will supersede platinum-based chemotherapy in the not-too-distant future,” he predicted. “If that is the case, where are we left with these definitions of platinum-eligible and cisplatin-eligible?” he asked. Dr Gupta agreed. “I think if EV-302 is a positive trial, platinum ineligibility will be a moot point, because everybody can get enfortumab vedotin plus pembrolizumab,” she said. “The question will then be what long-term toxicities we’ll see with that regimen and how that compares with gemcitabine plus carboplatin followed by avelumab.”

Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.

References

1. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer ‘unfit’ for cisplatin-based chemotherapy. J Clin Oncol. 2011;29:2432-2438. DOI: 1200/JCO.2011.34.8433
2. Chang SS, Bochner BH, ChouTR, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline (amended 2020). American Urological Association; 2020. Accessed May 6, 2022. https://www.auanet.org/documents/Guidelines/PDF/Muscle-Invasive-Bladder-Cancer-2020.pdf
3. Witjes JA (chair); Muscle-invasive and Metastatic Bladder Cancer Guidelines Working Group. EAU guidelines on muscle invasive and metastatic bladder cancer. European Association of Urology, 2022. Accessed May 6, 2022. https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer
4. Flaig TW (chair), Spiess PE (Vice-chair); NCCN Bladder Cancer Panel. NCCN Clinical Practice Guidelines in Oncology. Bladder cancer, version 1.2022. February 11, 2022. National Comprehensive Cancer Network; 2022. Accessed May 6, 2022. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
5. Sridhar SS. Is it time to redefine cisplatin ineligibility in metastatic urothelial cancer? Eur J Cancer. 2020;127:158-159. DOI: 1016/j.ejca.2019.12.019
6. Jiang, D.M., Gupta, S., Kitchlu, A. et al. Defining cisplatin eligibility in patients with muscle-invasive bladder cancer. Nat Rev Urol. 2021;18:104-114. DOI: 1038/s41585-020-00404-6
7. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. Food and Drug Administration (FDA); July 5, 2018. Accessed April 21, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-limits-use-tecentriq-and-keytruda-some-urothelial-cancer-patients
8. Gupta S, Sonpavde G, Grivas P, et al. Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). J Clin Oncol. 2019;37(7 suppl):Abstract 451. DOI: 1200/JCO.2019.37.7_suppl.451
9. Powles T, van der Heijden MS, Castellano D, et al; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588. DOI: 1016/S1470-2045(20)30541-6
10. Powles T, Csőszi T, Özgüroğlu M, et al; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;(7):931-945, DOI: https://doi.org/10.1016/S1470-2045(21)00152-2
11. Galsky MD, Arija JÁA, Bamias A, et al; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. DOI: 1016/S0140-6736(20)30230-0
12. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. DOI: 1056/NEJMoa2002788