Expert Sees More Cross-Disciplinary Care in Urothelial Cancer Management

Hahn, director of the medical oncology bladder program at Johns Hopkins School of Medicine, has been working closely with Howard I. Scher, MD, the D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan Kettering Cancer Center, over the past few years as traditional systemic anticancer therapies have moved into early phases of urologic care.

“It’s a very exciting time right now in both spectrums, urology and oncology,” he said. “We’re going to be seeing a lot more cross-discipline care.”

The “hype” around immuno-oncology has grown by leaps and bounds over the past few years, Hahn said. But does the reality match the narrative?

Results from KEYNOTE-045 suggests it does. For example, 2-year follow-up data from the phase III KEYNOTE-045 trial showed sustained improvements in overall survival (OS) with pembrolizumab (Keytruda) over chemotherapy in pretreated patients with locally advanced or metastatic urothelial cancer, according to findings presented at the 2018 Genitourinary Cancers Symposium.¹

Investigators stopped the trial prematurely after a planned interim analysis. The median OS was 10.3 months with pembrolizumab versus 7.4 months for chemotherapy (hazard ratio [HR], 0.73;P= .002) published in the New England Journal of Medicine. The 12-month OS rate was 43.9% versus 30.7%, in favor of pembrolizumab.²

“What got immunotherapy approved to stay in bladder cancer was the fact that this trial was the first trial to ever show an overall survival advantage versus chemotherapy in patients with advanced disease,” Hahn said. “We had never seen that despite the previous 30 years of trying with various chemotherapies and combinations.”

Patients with histologically or cytologically confirmed urothelial carcinoma who progressed after platinum-based chemotherapy were randomly assigned to 200 mg of pembrolizumab every 3 weeks (n = 270) or investigator’s choice of paclitaxel at 175 mg/m2, docetaxel at 75 mg/m², or vinflunine at 320 mg/m², each administered every 3 weeks (n = 272).

As assessed by blinded independent central review, the objective response rate was 21.1% versus 11.4% in favor of the pembrolizumab arm (P= .001). The median duration of response was not reached (range, 1.6+ to 15.6+ months) with pembrolizumab compared with 4.3 months (range, 1.4+ to 15.4+) with chemotherapy.

“About twice as many patients saw their tumors shrink: about 20% compared with 10%,” he said. “What was striking was that, while that’s not a high percentage of patients, if you were in that group that responded, those responses tended to be durable.

Immunotherapy in Muscle Invasive Bladder Cancer and Non-Muscle Invasive Bladder Cancer

Hahn pointed out that immunotherapy is generally better tolerated than chemotherapy. In KEYNOTE-045, the incidence of treatment-related adverse events (TRAEs) was lower with pembrolizumab for any grade (60.9% vs 90.2%) and grade 3-5 (15.0% vs 49.4%). The discontinuation rate resulting from TRAEs was 5.6% in the pembrolizumab arm and 11.0% in the chemotherapy arm.

With the success of ICIs in metastatic disease—not just pembrolizumab, but also atezolizumab (Tecentriq), durvalumab (Imfinzi), and others—investigators have sought to determine if these agents would produce better outcomes in patients with earlier-stage bladder cancer. Several ongoing studies are exploring whether immunotherapy could be effective in patients with muscle invasive or nonmuscle invasive bladder cancer (MIBC/NMIBC).

Investigators are evaluating immunotherapy agents in the adjuvant setting in a pair of phase III trials: IMvigor010 (NCT02450331) investigating atezolizumab and AMBASSADOR (NCT03244384) investigating pembrolizumab, as well as the phase II CheckMate 274 trial (NCT02632409) investigating nivolumab (Opdivo). AMBASSADOR is looking at patients with locally advanced MIBC, with results expected in 2019. The other trials are examining patients with high-risk MIBC following resection with results expected in 2020.

“If we move to the nonmuscle invasive space, this is where I think things get really exciting,” Hahn said.

Findings from an interim analysis of the ongoing single-arm, open-label phase II KEYNOTE-057 trial were presented at the European Society for Medical Oncology Congress 2018. The data showed encouraging antitumor activity with pembrolizumab monotherapy in patients with high-risk NMIBC that was unresponsive to Bacillus Calmette-Guérin who refused or were ineligible for cystectomy.³

The rate of complete response (CR) in the first 103 patients enrolled with carcinoma in situ with or without papillary disease was 38.8% (95% CI, 29.4%-48.9%) at 3 months. Eighty percent of patients had a CR duration lasting ≥6 months. The median time to CR was 12.4 weeks (95% CI, 10.4-19.3). Twenty-nine (72.5%) responders had ongoing responses. The median duration of CR had not been reached (range, 0-14.1+ months).

“One of the questions that I think we’ll see in follow-up presentations of [these] data...is the question about duration,” Hahn said. “These data are too early to give us insight into that, but they did give us a hint of the durability of the CRs.”

He noted that the CR rate at 6 months, based on these results, would be about 31%. According to International Bladder Cancer Group guidelines issued in 2016, a clinically meaningful 6-month CR rate for this patient population is 50%.⁴

Ronald de Wit, MD, PhD, group leader of the Experimental Systematic Therapy of Urogenital Cancers program at Erasmus MC Cancer Institute, Rotterdam, The Netherlands, presented results from 103 patients who received 200 mg of pembrolizumab every 3 weeks. Treatment continued until recurrence of high-risk NMIBC. If NMIBC was present at any assessment, patients discontinued treatment and entered survival follow-up. The primary endpoint was a CR, defined as absence of NMIBC.

The interim analysis used an enrollment cutoff to ensure adequate follow-up for response evaluation. The database cutoff was July 18, 2018, and the enrollment cutoff was April 1, 2018. Most (96.1%) patients had at least 1 adverse event (AE). The rate of grade 3-5 AEs was 26.2%, and the rate of grade 3-5 TRAEs was 12.6%.

TRAEs in ≥2 patients included pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), maculopapular rash (5.8%), arthralgia (4.9%), rash (4.9%), hyperthyroidism (3.9%), and nausea (3.9%). The most common grade 3-5 TRAEs were hyponatremia (2.9%) and arthralgia (1.9%). Immune-related grade 3-5 TRAEs experienced by 1 patient each were adrenal insufficiency, colitis, hypophysitis, pruritus, rash, and type 1 diabetes.

Hahn noted that the incidence of grade 3/5 TRAEs in KEYNOTE-057 is similar to that previously observed in the metastatic setting. Of the 3 deaths in the study, only 1, an incidence of autoimmune colitis, was related to treatment.

“That’s about what we see in all diseases,” Hahn said. “It’s about a 1% or less autoimmune-related potentially fatal event, and that’s something that has been consistent throughout.”

Urology Practice Must Accommodate Immunotherapy

Immunotherapy is still a relatively new phenomenon in the urology world, but its success has been clear. Hahn did not want to use the word “cure” because patients have only been followed for 3 to 4 years, but said, “Patients are alive longer than we have ever seen before.”

However, when considering whether it is possible, or practical, to use these agents in earlier stages of disease, he said there are also practice concerns to keep in mind. Use of these agents will require a major education component for urologists generally and for oncologists who are unfamiliar with NMIBC. Further, urology practices will have to think about infusion center and toxicity management infrastructure, their relationships with practitioners in other specialties, and the internal commitment to this treatment modality.

“How does your group feel about systemic therapy?” he asked. “It’s one thing to have a champion who wants to do it and is going to take on doing it for their patients, but who’s going to take the call on Friday at 4:30 pm when you’re out on vacation and your partner is covering? Those things need to be talked about.

References:

1. Bellmunt J, De Wit R, Vaughn DJ, et al. Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab (pembro) vs investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (UC).J Clin Oncol.2018;36(suppl 6S; abstr 410). doi: 10.1200/JCO.2018.36.6_suppl.410.
2. 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.
3. de Wit R, Kalkami GS, 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. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. oncologypro.esmo.org/Meeting-Resources/ESMO- 2018-Congress/Pembrolizumab-for-High-Risk-HR-Non-Muscle-Invasive-Bladder-Cancer-NMIBC-Unresponsiveto- Bacillus-Calmette-Guerin-BCG-Phase-2-KEYNOTE-057-Trial
4. Kamat AM, Sylvester RJ, Böhle A, et al. Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the International Bladder Cancer Group.J Clin Oncol.2016;34(16):1935- 1944. doi: 10.1200/JCO.2015.64.4070.