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The introduction of effective systemic immunotherapies has been the most important innovation for the management of advanced urothelial cancer since the establishment of cisplatin-based chemotherapy several decades ago. Antibodies targeting immune checkpoints like the programmed cell death protein-1 (PD-1) and one of its ligands (PD-L1) are now approved, offering an alternative approach to both salvage therapy and treatment for patients who are unfit for cisplatin.
In 2018, emerging data from key clinical trials, including updates to pivotal trials in recurrent disease and in the first-line setting for cisplatin-ineligible patients, have helped to refine the use of immune checkpoint inhibitors within the standard of care for urothelial cancer. In addition, significant advances have been made in patient selection to improve outcomes with immune checkpoint inhibitors, as well as in the recognition and management of immune-related adverse events.
Single-agent checkpoint inhibitors in the recurrent disease setting
Five immune checkpoint inhibitors are now available for the treatment of patients with advanced urothelial cancer that has recurred after treatment with platinum-based chemotherapy: Atezolizumab, durvalumab, nivolumab, pembrolizumab, and avelumab. However, most of these approvals were granted on a conditional basis, supported by single-arm studies.
To date, only two randomized trials have been conducted to confirm a survival benefit for salvage immunotherapy. The first of these was KEYNOTE-045, which demonstrated improved overall survival (OS) for pembrolizumab over chemotherapy (HR 0.73, P = .002) in the intent-to-treat population.1 Two-year follow-up of KEYNOTE-045 continued to affirm this benefit (median OS, pembrolizumab vs chemotherapy, 10.3 months vs 7.3 months, HR 0.70, P = .00017).2 Subgroup analyses also showed that the benefit from pembrolizumab was consistent irrespective of primary tumor site (upper tract vs lower tract) and PD-L1 combined positivity score (CPS, ≥10% vs <10%).2
The PD-L1 antibody atezolizumab was given an accelerated approval from the United States Food and Drug Administration (US FDA) on the basis of findings from the phase II IMvigor210 study, which showed encouraging median OS in the intent-to-treat population. In the subgroup of patients with higher (≥5%) PD-L1 staining on tumor-infiltrating immune cells (IC2/3), median OS was 11.4 months, with a 12-month OS rate of 48%.3 This led to the selection of OS in the IC2/3 population as the primary endpoint in the confirmatory phase III IMvigor211 trial.4 Median OS did not differ between the two treatment arms in this group (atezolizumab vs chemotherapy, 11.1 months vs 10.6 months, HR 0.87, P = .41), suggesting that ≥5% PD-L1 expression on immune cells is a prognostic, yet not predictive, biomarker for these patients.4
Ongoing investigations in first-line, advanced urothelial cancer
The efficacy and tolerability of immune checkpoint inhibitors has driven substantial interest in moving these agents to first-line therapy. This was first realized in patients who are ineligible for cisplatin-based therapy. Both pembrolizumab and atezolizumab have been approved in this setting based on open-label, nonrandomized studies. IMvigor210 included a cohort of 119 cisplatin-ineligible patients with untreated metastatic urothelial cancer.5 The objective response rate (ORR) with atezolizumab was 24%, and median OS was 15.9 months.5
The KEYNOTE-052 is a single-arm, phase II study that has included 370 patients in an extended follow-up.6 This trial has a greater proportion of patients with ECOG PS 2 compared with the untreated cohort of IMvigor210 (42% vs 20%), as well as a higher proportion of patients with visceral metastases (85% vs 65%).5,6 The ORR was 28.9%, with median progression-free survival (PFS) of 2.3 months, and median OS of 11.5 months.6
These findings suggest that OS with immunotherapy is at least comparable to OS with chemotherapy. Multiple randomized studies are ongoing to assess the benefit of PD-1 axis inhibitors, either as single agents or in combination with chemotherapy or CTLA-4 antibodies.7–10 Although no data have yet been published from these studies, in July 2018 the FDA and European Medicines Agency (EMA) amended the labels for pembrolizumab and atezolizumab to allow their use in the frontline setting only for PD-L1–positive patients.11,12
Breaking ground in immunotherapy for operable bladder cancer
Although local therapy is an option for patients with invasive, operable bladder cancer, outcomes remain poor, driving a need for newer treatment approaches. Neoadjuvant chemotherapy offers a modest OS benefit (a 5% absolute improvement in 5-year OS rates) to patients with these tumors.13 There has also been interest in testing the role of immune checkpoint inhibitors in the perioperative setting. In 2018, the phase II ABACUS study showed the feasibility of neoadjuvant atezolizumab in muscle-invasive bladder cancer.14 Atezolizumab led to a pathologic complete response (PCR) rate of 29% in the 62 patients enrolled in the study, and 39% were successfully downstaged to non-muscle-invasive disease.14 Furthermore, these responses appeared to be enriched in the PD-L1 positive subgroup of patients, with 10 of 25 (40%) achieving a PCR.14
Another study, KEYNOTE-057, assessed neoadjuvant pembrolizumab in patients with high-risk non-muscle-invasive bladder cancer that was unresponsive to Bacillus-Calmette Gurin.15 Patients in this study were either ineligible for or refused cystectomy, and they were enrolled in two cohorts: Carcinoma in situ with or without papillary disease, and papillary disease without carcinoma in situ. An interim analysis presented at ESMO 2018 focused on the first cohort of patients.15 The primary objective for this cohort was complete response, which was shown in 40 of the 103 enrolled patients (38.8%).15
Evolving solutions to practical challenges in immunotherapy
Optimal patient selection has been controversial in the field of bladder cancer management since the initial approval of atezolizumab. In particular, defining PD-L1 positivity remains an area of substantial debate, since each of the five approved PD-1 axis inhibitors has its own distinct methods for testing and interpreting PD-L1 expression, with variations in immunohistochemical methods for staining, the tissue source of interest (tumor and/or tumor-infiltrating immune cells), and cutoffs to connote a PD-L1–positive specimen.16 Moreover, different clinical trials had varying specifications for using archival versus fresh tissue samples, which may have impacted the interpretation of the biomarker.16
This is further complicated by the apparent lack of predictive utility of PD-L1 expression in the recurrent disease setting. For example, in IMvigor211, enrolling only patients with IC2/3 PD-L1 expression appeared to select for those with generally better OS in both the chemotherapy and immunotherapy arms, with no significant benefit from atezolizumab compared with chemotherapy.4 In KEYNOTE-045, patients achieved a substantial OS benefit regardless of whether they had a PD-L1 CPS of ≥10 or <10.2 In contrast, the regulatory agencies’ recent amendments to the first-line label for pembrolizumab and atezolizumab points to important data – thus far unpublished – suggesting that PD-L1 is an important selection criterion, adding further confusion and controversy that has yet to be resolved.11,12
The challenges associated with PD-L1 evaluation have led to the exploration of alternative biomarkers. Tumor mutational burden has recently emerged as a potential biomarker for several applications of immunotherapy.17 Notably, IMvigor211 included an exploratory analysis of outcomes based on tumor mutational burden.4 Patients with tumors above the median tumor mutational burden appeared to have better outcomes with atezolizumab (median OS, atezolizumab vs chemotherapy, 11.3 months vs 8.3 months, HR 0.68), whereas this apparent benefit was not present in the mutational burden–low population (median OS, atezolizumab vs chemotherapy, 8.3 months vs 8.1 months, HR 1.00).4
Safety and tolerability of immune checkpoint inhibitors is another ongoing challenge that is continuing to be better understood. Although these agents are generally associated with lower rates of serious adverse events, they nevertheless pose unique safety risks. In particular, immune-related adverse events (irAEs) can present as an inflammatory reaction in almost any organ system. Moreover, these adverse events often lag the initial dosing by weeks or months, depending on the adverse event in question.18
Recently, the real-world, prospective, phase IIIb SAUL study provided the most extensive look to date for the safety and efficacy of atezolizumab in second-to-fourth line treatment.19 Overall, 13% of the 997 patients who received atezolizumab experienced a treatment-related grade ≥3 adverse event, and this rate was consistent in the patient subgroups who had renal impairment (7%), concomitant steroid usage (10%), and ECOG PS 2 (13%).19 Of 35 patients with autoimmune disease, 9 (26%) experienced a grade ≥3 treatment-related adverse event.19 These findings show that in a real-world group of patients, atezolizumab’s safety profile is consistent with the known clinical trial experience.
2018 was an important year of refinement for immunotherapy in bladder cancer. For now, the use of immunotherapy in bladder cancer continues to rest on second-line immune checkpoint inhibitors, without a significant need to select patients using PD-L1. In first-line therapy, clinicians can continue to use pembrolizumab or atezolizumab in cisplatin-ineligible patients, providing they test positive for PD-L1 using the appropriate test for each agent. With the help of pivotal studies coming over the next year, hopefully the questions surrounding patient selection, particularly in the first-line setting, will be addressed. Furthermore, given the success of chemotherapy-immunotherapy combinations in non-small cell lung cancer management, it will be very interesting to see whether there is similar benefit in bladder cancer.
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- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
- Bellmunt J, de Wit R, Vaughn DJ, et al. Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab versus investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer. J Clin Oncol. 2018;36(6_suppl): Abstract 410.
- Rosenberg JE, Hoffman-Censits J, Powles T, 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. Lancet. 2016;387(10031):1909-1920.
- Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
- Balar A V, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
- Vuky J, Balar AV, Castellano DE, et al. Updated efficacy and safety of KEYNOTE-052: A single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). J Clin Oncol. 2018;36(15_suppl): Abstract 4524.
- National Institutes of Health. A phase III, multicenter, randomized, placebo-controlled study of atezolizumab (anti−PD-L1 antibody) as monotherapy and in combination with platinum-based chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma. https://clinicaltrials.gov/ct2/show/NCT02807636. Accessed March 20, 2019.
- National Institutes of Health. A phase III, randomized, open-label, controlled, multi-center, global study of first-line MEDI4736 (durvalumab) monotherapy and MEDI4736 (durvalumab) in combination with tremelimumab versus standard of care chemotherapy in patients with unresectable stage IV urothelial cancer. https://clinicaltrials.gov/ct2/show/NCT02516241. Accessed March 20, 2019.
- National Institutes of Health. A phase III randomized, controlled clinical trial of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy in subjects with advanced or metastatic urothelial carcinoma. https://clinicaltrials.gov/ct2/show/NCT02853305. Accessed March 20, 2019.
- National Institutes of Health. A phase 3, open-label, randomized study of nivolumab combined with ipilimumab, or with standard of care chemotherapy, versus standard of care chemotherapy in participants with previously untreated unresectable or metastatic urothelial cancer. https://clinicaltrials.gov/ct2/show/NCT03036098. Accessed March 20, 2019.
- EMA restricts use of Keytruda and Tecentriq in bladder cancer [press release]. 01/06/2018. https://www.ema.europa.eu/en/news/ema-restricts-use-keytruda-tecentriq-bladder-cancer. Accessed March 19, 2019.
- FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients [press release]. 07/05/2018. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm612484.htm. Accessed March 19, 2019.
- Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202-205.
- Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). J Clin Oncol. 2018;36(suppl): Abstract 4506.
- de Wit R, Kulkarni G, Uchio E, et al. Pembrolizumab for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG): Phase 2 KEYNOTE-057 trial. Ann Oncol. 2018;29(suppl_8): Abstract 864O.
- Powles T, Necchi A, Rosen G, Hariharan S, Apolo AB. Anti–programmed cell death 1/ligand 1 (PD-1/PD-L1) antibodies for the treatment of urothelial carcinoma: State of the art and future development. Clin Genitourin Cancer. 2018;16(2):117-129.
- Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124-128.
- Haanen JBAG, Carbonnel F, Robert C, et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142.
- Sternberg CN, Loriot Y, James N, et al. Primary results from SAUL, a multinational single-arm safety study of atezolizumab therapy for locally advanced or metastatic urothelial or nonurothelial carcinoma of the urinary tract. Eur Urol. 2019 Mar 22. [Epub ahead of print].
Stay informed on key data in immune-oncology for non-small cell lung cancer, melanoma, and bladder cancer reported data. Don’t miss out!
Recent Reflections on Immuno-Oncology: Bladder Cancer
This educational activity is designed to meet the needs of medical oncologists and other healthcare professionals involved in the treatment of patients with lung cancer, bladder cancer, and melanoma.
After successful completion of this educational activity, participants should be able to:
- Evaluate clinical trial data assessing the efficacy and safety of immune checkpoint inhibitors for the management of patients with solid tumors
- Develop optimal treatment plans utilizing immune checkpoint inhibitors for the treatment of solid tumors
- Assess the rationale for using immune checkpoint inhibitors, alone, and in combination with chemotherapy or other novel agents, for the treatment of solid tumors
- Formulate treatment plans to manage immune-related adverse events associated with the treatment with immune checkpoint inhibitors
This educational activity is supported by a grant from Merck Sharp and Dohme Corp.
In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and prIME Oncology. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Lung newsletter: 0.5
Bladder newsletter: 0.75
Melanoma newsletter: 0.5
This activity is jointly provided by Postgraduate Institute for Medicine and prIME Oncology.
Method of Participation
Estimated time to complete activity: 1.75 hours
To contact Postgraduate Institute for Medicine please visit www.pimed.com.
Disclosure of Relevant Financial Relationships
Postgraduate Institute for Medicine (PIM) and prIME Oncology require instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
Postgraduate Institute for Medicine Planners and Managers have disclosed no relevant financial relationships.
The employees of prIME Oncology have disclosed:
- Briana Betz, PhD (scientific content reviewer/planner) –(scientific content reviewer/planner) – worked on non–CME certified projects in the last 12 months supported by Helsinn Healthcare, ImmunoGen, Karyopharm Therapeutics, Novartis, Pfizer, and TG Therapeutics
- Zach Hartman, PhD (author) – no relevant financial relationships
- Heather Tomlinson, ELS (editorial content reviewer) – worked on non–CME certified projects in the last 12 months supported by AstraZeneca, Clovis Oncology; F. Hoffmann-La Roche Ltd; ImmunoGen; Merck KGaA, Darmstadt, Germany; Pfizer; Novartis Oncology; Puma Biotechnology; and Tesaro
Disclosure Regarding Unlabeled Use
This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration or European Medicines Agency. Please refer to the official prescribing information for each product discussed for discussions of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.