Checkpoint Therapy Is the Primary Treatment Choice for Patients With Bladder Cancer, Says Petrylak

Daniel Petrylak, MD

Daniel Petrylak, MD

Daniel Petrylak, MD, recently spoke on the treatment considerations and decisions he makes when treating patients with bladder cancer. Petrylak, director of prostate and genitourinary medical oncology and the Prostate Cancer Translational Research Group, Yale Cancer Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

September 2016

A 66-year-old woman was referred by urology after evaluation for gross hematuria. Her past medical history showed chronic obstructive pulmonary disorder, mild hypertension, and coronary artery disease (no prior myocardial infarction), in addition to a 40-year smoking history. Her creatinine clearance levels were 1.2 mL/min.

A cystoscopy revealed a nodular 8-cm mass along posterior bladder wall. Transurethral resection specimens of the bladder showed high-grade urothelial carcinoma invading the muscularis propia. A CT scan of the abdomen and pelvis was negative for lymphadenopathy or distant metastases. Her initial diagnosis was muscle-invasive bladder cancer, urothelial origin.

What are your general impressions of this patient?

This is a woman who has muscle-invasive bladder cancer. She has as a creatinine clearance of 1.2 mL/min, which would mean that she would not be a bad candidate for neoadjuvant chemotherapy.

What factors influence your therapeutic approach?

When deciding on a therapeutic approach, one needs to think about the performance status, renal function, as well as the comorbidities. This patient received DD MVAC for 4 cycles.

The patient received neoadjuvant platinum-based chemotherapy (dose-dense methotrexate, vinblastine, doxorubicin [Adriamycin], and cisplatin [DD MVAC]) for 4 cycles.

October 2016

The patient underwent radical cystectomy and pathology demonstrated pT3N0 high-grade urothelial cancer. She was enrolled to a clinical trial of checkpoint inhibitor versus observation, randomized to observation.

Four months later she complained of shortness of breath. A CT scan showed multiple bilateral pulmonary nodules and metastatic urothelial cancer confirmed by interventional radiology biopsy.

She had an ECOG performance status of 0 but continued to smoke 1+ packs per day. Her liver function tests and creatinine clearance levels were within normal limits.

What would you consider as second-line therapy for this patient?

She has high-risk urothelial carcinoma with a T3b stage. At the time, she underwent a cystectomy and she was asked to enter in a randomized trial of immune checkpoint inhibition versus observation. She went on observation, and she relapsed 4 months after the cystectomy. In that situation, we would give a checkpoint, which is considered to be second-line treatment. Checkpoint therapy would be the right way to go about this.

What factors influence the decision for second-line therapy?

Previous treatment greatly influences the options. Additionally, there was a phase I/II trial that looked at durvalumab (Imfinzi) in patients with metastatic urothelial carcinoma.¹There does seem to be correlation with PD-L1 expression and a better survival in patients who have PD-L1 high expression; it’s 72% versus 51% for patients with PD-L1—low expression at 6 months. At 12 months, it is 52% versus 41%. It does seem to correlate with PD-L1 expression.

Which agents would you consider?

All the approved agents are similar. The only agent that has level 1 evidence is pembrolizumab (Keytruda). For me, that would be the treatment of choice. There was a randomized phase III trial supporting pembrolizumab; however, all the other agents seem to have similar response rates.²Of note, atezolizumab (Tecentriq) did have a failed phase III trial.

Is this patient a candidate for chemotherapy?

Eventually, this patient might be a candidate as a third-line agent. But because we have an FDA-approved agent in this setting, I would only consider checkpoint therapy as the primary treatment choice.

The patient received pembrolizumab.

What would you offer this patient upon progression on pembrolizumab?

I would offer her single-agent chemotherapy; however, clinical trials would be my first choice. There is no proven value of any of these agents; they all have 20% response rates, so you have to look at the toxicities [associated with these agents]. If she has nephropathy, you probably wouldn’t give her pemetrexed. If she develops renal insufficiency, you probably wouldn’t give a taxane-based chemotherapy.

Case 2

A 62-year-old man presented with dizziness and hematuria. A chest x-ray and CT later revealed a 3.5-cm mass and multiple lung metastases. A ureteroscopic biopsy/pathology confirmed stage IV transitional cell carcinoma. He had an ECOG performance status of 1, and his creatinine clearance levels were 51 mL/min.

What are your general impressions of this patient?

In this case, PD-L1 testing would be useful. A recent FDA alert said that patients who have low expression of PD-L1 have an inferior survival when treated with single-agent immune checkpoint inhibitors compared to those who receive chemotherapy.³I would do a PD-L1 test on this patient to find out whether they are PD-L1—negative or not.

What treatment are you most likely to offer this patient?

There are clinical trials that I would consider for this patient. Randomized studies have looked at a checkpoint inhibitor plus chemotherapy versus chemotherapy alone. That is either atezolizumab or pembrolizumab in this setting. Those are studies that I would consider for this particular patient at this point.

The patient received atezolizumab and he achieved a complete response after 6 cycles. After cycle 10, the patient complained of worsening fatigue, dyspnea on exertion, and cough.

What would your approach be upon disease progression?

In this case, he did receive atezolizumab, and then he started to progress. One thing you could consider would be to go on standard-of-care chemotherapy afterwards, such as gemcitabine/carboplatin. If the patient progresses after gemcitabine/carboplatin, you could consider other clinical trials.

The patient has no signs of infection and is up to date on his flu vaccine. A chest x-ray confirmed grade 2 pneumonitis.

What is your approach toward management of grade 2 pneumonitis related to checkpoint inhibitor therapy?

Steroids. If it is grade 1, you would stop treatment.

Will all patients receive immunotherapy either upfront or after progression in the future?

Yes, I think eventually everyone is going to receive it upfront. If you look at sequencing, I think they are going to be given with standard-of-care upfront.

Will some patients be able to forgo chemotherapy?

When we see some of these other agents that show activity, it may be that around a quarter of patients will be able to forgo chemotherapy. But I think, for everyone, chemotherapy will be an effective alternative once these patients progress.

With so many to choose from, which checkpoint inhibitor will be the right choice?

The choice is probably pembrolizumab, based on the randomized trial. But again, all of them seem to have similar response rates.

What is important to know about toxicity management in bladder cancer?

The earlier you recognize it and treat it, the better off you are. If it gets to grade 3/4, you may not be able to give the patient subsequent checkpoint inhibition therapy. That may impact the survival.

References:

1. Hahn NM, Powles T, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC).J Clin Oncol. 2017;35(15 suppl; abstr 4525). doi: 10.1200/JCO.2017.35.15_suppl.4525.
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/NEDJMoa1613683.
3. 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 [news release]. Rockville, MD: FDA; June 20, 2018. fda.gov/Drugs/DrugSafety/ucm608075.htm.