Findings Set Stage for Expanded Immunotherapy Role in Bladder Cancer

OncologyLive, Vol. 19/No. 13, Volume 19, Issue 13

Researchers now are turning their attention toward earlier disease settings involving patients who are refractory to standard therapies in nonmuscle-invasive bladder cancer or who are poor candidates for surgery in muscle-invasive bladder cancer.

Arjun V. Balar, MD

After a series of rapid approvals, checkpoint blockade immunotherapy has emerged as a key component of an increasingly complex treatment landscape in advanced and metastatic urothelial carcinoma (mUC). Researchers now are turning their attention toward earlier disease settings involving patients who are refractory to standard therapies in nonmuscle-invasive bladder cancer (NMIBC) or who are poor candidates for surgery in muscle-invasive bladder cancer (MIBC).

Those were the trends that Arjun V. Balar, MD, described during a presentation at this year’s American Urological Association (AUA) Annual Meeting. Balar, a leading immunotherapy investigator, said extended follow-up has confirmed noteworthy benefits for patients with advanced disease who are cisplatin-ineligible or who progress on a platinum-based regimen.

Balar said he is encouraged about the future. “Immunotherapy is a viable treatment option for the majority of our patients,” said Balar, who is the director of the Genitourinary Medical Oncology Program at NYU Langone Medical Center in New York. “Although the pace of progress of drug development in bladder cancer is unprecedented, there remain unmet needs, including the need for reliable biomarkers and more studies exploring combination therapies.”

To date, 5 agents that target the PD-1/PD-L1 pathway have received FDA approval for the treatment of UC, the most common type of bladder cancer. These include the anti—PD-1 antibodies nivolumab (Opdivo) and pembrolizumab (Keytruda) and the anti–PD-L1 antibodies atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio). All of the drugs are approved for patients with locally advanced or metastatic UC whose disease progresses during or after platinum- containing chemotherapy. Pembrolizumab and atezolizumab also are approved for patients in this disease state who are not eligible for cisplatin- containing regimens (Figure1).

Figure. Current Therapeutic Paradigm in Bladder Cancer1

Metastatic Setting

However, the FDA announced on June 20 that the use of the drugs in cisplatin-ineligible patients should depend upon PD-L1 expression level based upon observed results in ongoing clinical trials.2 For cisplatin-ineligible patients, pembrolizumab is now indicated for those with a PD-L1 expression combined positive score (CPS) ≥10%. Atezolizumab is now approved for cisplatin-ineligible patients whose PD-L1 expression is ≥5% on tumor-infiltrating immune cells (ICs). Both drugs also are indicated for patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.Second-Line Therapy

Atezolizumab became the first approved immunotherapy for UC in May 2016 based on results from IMvigor210, a 2-cohort phase II study in patients with inoperable locally advanced or metastatic UC, said Balar. Cohort 1 consisted of 119 cisplatin- ineligible, and cohort 2 comprised 310 patients with platinum-treated metastatic disease.

Among patients who had been previously treated with platinum therapy, the median time to first response was 2.1 months, with a range of 1.6 to 8.3 months. Additional complete responses (CRs) and partial responses (PRs) were observed with longer follow-up, including conversions of 5 PRs to CRs and 2 with stable disease to PRs. Median follow-up was reported as 17.5 months (range, 0.2-21.1+).3

“The continuous treatment is feasible with immunotherapy, but not really feasible with chemotherapy, largely because of toxicity,” said Balar. “Ongoing responses in this trial are important, about 20 months or more. You typically never see this in second-line bladder cancer, which we consider a uniformly fatal malignancy.” Responses were ongoing in 37 of 46 (80%) patients per RECIST criteria and 46 of 60 (77%) patients per modified RECIST criteria. Dreicer and colleagues reported that the median duration of response was not reached in any group when results were stratified for PD-L1 status scored on tumor-infiltrating ICs.3

Extended follow-up results have also been reported for pembrolizumab in the pivotal KEYNOTE-045 trial. Updated overall survival (OS) rates presented at the European Society for Medical Oncology meeting and the Genitourinary Cancers Symposium 2018 meeting demonstrated HRs of 0.73 (P = .0022) at 14.1 months’ median follow-up and 0.70 (P = .00017) at 28 months follow-up, said Balar.

The objective response rate (ORR) for the total population in this study was 21.1% (95% CI, 16.4%-26.5%) in the pembrolizumab group compared with 11.4% (95% CI, 7.9%-15.8%) in the chemotherapy group.4 In the study, the combined positive score was defined as the percentage of PD-L1—expressing tumor and infiltrating ICs relative to the total number of tumor cells. “What’s interesting is that in the PD-L1–positive population, the response rate is still 21%,” Balar said. PD-L1 positivity was designated as ≥10% or more.

“This is unusual because other studies have shown a response [associated with] PD-L1 expression, but for this study, the response rates weren’t enriched by PD-L1 status. This strongly argues against PD-L1 testing in the second-line setting because it doesn’t help us that much, especially considering how inferior chemotherapy is in this population,” Balar added.

First-Line Therapy

In the first-line metastatic setting, cisplatin improves survival; however, 50% to 70% of patients are ineligible because of comorbidities, specifically poor performance status (PS), renal dysfunction, neuropathy, hearing loss, and heart failure. “We often make the judgment whether a patient can tolerate this platinum treatment largely based on clinical factors,” said Balar. “In the clinic, patients who are cisplatin-ineligible are given gemcitabine/ carboplatin if they are chemotherapy eligible, but outcomes are still very poor, with 40% or more of patients never receiving treatment.”

Turning to cohort 1 of the IMvigor210 study, Balar said patients received 1200-mg atezolizumab until progression. Cisplatin ineligibility was based on 1 or more criteria: renal impairment, ≥ grade 2 hearing loss or peripheral impairment, or Eastern Cooperative Oncology Group PS of 2.

Balar pointed out that in DeSantis et al, patients treated with gemcitabine and carboplatin had an OS rate of 37% at 1-year and no long-term survivors despite a response rate of 36%.5 He compared these findings with KEYNOTE-052, in which the efficacy and safety of pembrolizumab as first-line therapy for cisplatin- ineligible mUC was demonstrated. Patients achieved a median OS of 15.9 months (95% CI, 10.4-not estimable) and an OS of 57% at 12 months.6 At 17.2 months’ median follow-up, the ORR was 23% (95% CI, 16%-31%), the CR rate was 9% (n = 11), and 19 of 27 responses were ongoing. In the trial, the median response duration was not reached.6 With longer follow-up, updated findings demonstrated an ORR of 29%, 10 additional CRs, and 9 additional PRs, said Balar.

Balar emphasized the baseline characteristics of the patients involved with the study (N = 370), which suggest that the treatable population for the agent is larger than originally expected. The median age of patients was 74 years, including 107 patients (29%) who were over 80 years. “We typically don’t include that many patients who are elderly,” said Balar. “In addition, 42% of patients had poor performance status, including 85% with visceral metastatic disease.”6

Despite those positive results, ongoing phase III studies have raised questions about which cisplatin-ineligible patients are best suited for frontline immunotherapy. The FDA said its decision to change the labeling for pembrolizumab and atezolizumab as frontline therapy for this population was based on an assessment conducted by a data monitoring committee (DMC) for the phase III KEYNOTE-361 and IMvigor130 studies.

The KEYNOTE-361 (NCT02853305) and the IMvigor130 (NCT02807636) studies are exploring pembrolizumab and atezolizumab, respectively, with or without chemotherapy compared with chemotherapy or the immunotherapy alone.

The DMC identified that patients with PD-L1— low status had decreased OS in the single-agent immunotherapy arms compared with chemotherapy. Both trials have stopped enrolling patients with PD-L1–low status to the monotherapy arms. Other arms of the trials will remain open to patients, regardless of PD-L1 status.

Potential Combos in Other Settings

The FDA action came after Balar delivered his presentation at AUA. Balar, however, noted that questions about the ideal patient population and sequencing continue to follow checkpoint inhibitors in mUC. “In the clinic, patients can respond exceptionally well and have an almost Lazaruslike response, but for patients who don’t respond, they can deteriorate very quickly,” he said. “This is where we need to improve [our understanding] of the use of combination therapies.”In MIBC, chemoradiation (CRT) is the standard of care for patients who are not candidates for surgery or who do not want to undergo radical cystectomy, Balar noted. The use of radiation may enhance immunotherapy in sequenced or combined therapy. “Several studies have shown that radiation can induce immunogenic cell death and work in synergy with checkpoint blockade,” he said.7

For example, in PACIFIC,8 patients with stage III non—small cell lung cancer who had not progressed following platinum-based concurrent CRT therapy were randomized to receive either durvalumab or placebo. Compared with placebo, patients who received durvalumab as maintenance therapy after CRT demonstrated better median progression- free survival (16.8 vs 5.6 months; HR, 0.52; P <.0001), time to distant metastasis or death (23.2 vs 14.6 months; HR, 0.52; P <.0001), and ORR (28% vs 16%; HR 1.78; P <.001).

There is a lack of evidence establishing the safety combining pembrolizumab, gemcitabine, and hypofractionated radiation therapy in the management of patients with MIBC who are not candidates for or who decline radical cystectomy, said Balar. He highlighted a phase II trial that could enroll up to 54 patients (NCT02621151). An initial safety lead-in cohort of 3 to 6 patients will receive pembrolizumab every 2 to 3 weeks at 200 mg. If no patients or only 1 patient in the lead-in cohort experiences a dose-limiting toxicity, the trial will continue to the phase II portion and enroll an additional 48 patients for efficacy evaluation.

Patients will receive external beam radiation therapy (EBRT) of 52 Gy in 20 fractions over 4 weeks, gemcitabine 27 mg/m2 twice weekly for 4 weeks concurrent with EBRT, and pembrolizumab 200 mg every 3 weeks for 3 doses starting on the first day they receive EBRT.

In a planned phase III trial involving concurrent chemoradiotherapy and atezolizumab, patients will be stratified by chemotherapy regimen, radiation field, performance status, and clinical stage prior to randomization.9 Patients will be randomized 1:1 to receive concurrent CRT versus CRT plus atezolizumab. The primary endpoint is disease-free survival, and secondary endpoints include OS at 5 years, metastasis-free survival, and clinical response in 5 months.

The use of anti—PD-L1 agents in NMIBC is also undergoing investigation in a number of clinical trials. In NCT02792192, the safety and pharmacology of atezolizumab in combination with Bacillus Calmette-Guérin (BCG) is undergoing investigation in high-risk patients with NMIBC; atezolizumab also will be studied in 2 phase II trials in nonmetastatic transitional cell carcinoma (NCT02451423) and in recurrent BCG-unresponsive patients with NMIBC (NCT02844816).

Durvalumab is being studied in a 3-cohort trial called ADAPT-BLADDER (NCT03317158) and in BCG-refractory patients (NCT02901548). In CheckMate-9UT, nivolumab is undergoing evaluation in BCG-unresponsive patients with NMIBC (NCT03519256). In KEYNOTE-057, pembrolizumab is under study in high-risk patients with NMIBC (NCT02625961). Patients with intermediate- risk recurrence of NMIBC will be recruited for a phase I/II marker lesion study evaluating the safety, tolerability, and efficacy of pembrolizumab (NCT03167151).

Balar concluded that there was great potential for immunotherapy in localized bladder cancer including for patients with nonmuscle invasive disease or for those with MIBC who are ineligible for or refuse surgery.

References

  1. Balar A. Systemic immunotherapy in urothelial cancer―where are we now and where are we going? Presented at: 113th Annual Meeting of the American Urological Association; San Francisco, CA; May 20, 2018.
  2. FDA alerts health care professionals and oncology clinical investigators about an efficacy issue identified in clinical trials for some patients taking Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as monotherapy to treat urothelial cancer with low expression of PD-L1. US Food and Drug Administration website. fda.gov/Drugs/DrugSafety/ucm608075.htm. Updated June 20, 2018. Accessed June 21, 2018.
  3. Dreicer R, Hoffman-Censits JH, Flaig TW, et al. Updated efficacy and >1-y follow up from IMvigor210: atezolizumab (atezo) in platinum (plat) treated locally advanced/metastatic urothelial carcinoma (mUC). J Clin Oncol. 2016;34(suppl 15):4515. meetinglibrary.asco.org/record/135721/abstract.
  4. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.
  5. De Santis M1, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191-199. doi: 10.1200/JCO.2011.37.3571.
  6. Balar AV, 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. doi: 10.1016/S0140-6736(16)32455-2.
  7. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013 Feb 20;105(4):256-65. doi: 10.1093/jnci/djs629.
  8. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Singh P, Lerner SP, Efstathiou E, et al. Phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer. Presented at: SWOG Spring 2018 Group Meeting; San Francisco, CA; April 11-14, 2018. swog.org/sites/default/files/docs/2018-05/Spr18AgendaBook.pdf.