Liu Discusses Treatments in Multiple Lines for Bladder Cancer

Sandy Ting Liu, MD

During a Targeted Oncology Case Based Peer Perspectives event, Sandy Ting Liu, MD, assistant Professor of Medicine Hematology-Oncology, Ronald Reagan UCLA Medical Center in Los Angeles, CA, discussed the case of a62-year-old male patient with bladder cancer.

Targeted Oncology™: At this point, would you consider immunotherapy for treating this patient?

LIU: If they’re cisplatin ineligible, they can get atezolizumab [Tecentriq] or pembrolizumab [Keytruda], if their tumor is PD-L1 positive. It’s important to know their PD-L1 expression status. Performance status is also important to determine your treatment for the patient. Intolerance to prior therapy is also a consideration.

Would you consider a clinical trial for this patient?

At my [institution], yes. We always try to find a trial for patients, if possible.

How would you treat this patient with first-line metastatic disease?

This patient is young with a creatinine clearance of 51 mL/min. I tend to push for cisplatin, maybe split the dose of cisplatin on day 1 and day 8, since it is currently the gold standard.

What dosing options are available for patients in this setting who receive gemcitabine/cisplatin?

This patient received dose-dense gemcitabine plus cisplatin. [There is a] regimen that is still in clinical trials, but basically, patients receive split-dose cisplatin on day 1 and day 2, and then they get gemcitabine at 2.5 times the usual dose on day 1, for every 2 weeks. But again, for this patient, I would just give him split-dose cisplatin at the usual every-3-week cycle.

Would you repeat PD-L1 expression testing or other biomarker testing on this patient?

I would always consider redoing the biopsy upon progression. It’s not necessary to do the biopsy, but it may give us additional information. It won’t necessarily change management.

Which PD-1 or PD-L1 inhibitor would you select here?

For patients with recurrent disease after chemotherapy, there have been 5 FDA-approved PD-1/PD-L1 inhibitors…since May of 2016, with both atezolizumab and pembrolizumab also approved as first-line therapy for patients who are ineligible to receive platinum chemotherapy, or cisplatin, and whose tumors express PD-L1.¹ In the absence of any head-to-head comparison among the 5 different agents, their activity is pretty similar [TABLE on page 20].^2-6

KEYNOTE-045 [NCT02256436] with pembrolizumab is the only phase 3 study that showed a median overall survival [OS] benefit of 10.3 months with pembrolizumab versus 7.4 months with chemotherapy.⁶ The rest of the studies with atezolizumab, nivolumab [Opdivo], durvalumab [Imfinzi], and avelumab [Bavencio] showed an objective response rate between 14% and 20% and a median OS of between 6.5 and 18.0 months. About 15% to 20% of the patients have a durable long-term survival.^2-5

Just to put this in perspective, the response rate for second-line chemotherapy with docetaxel is 8% or less and the duration of response is about 3 to 6 months. These immunotherapies have outperformed chemotherapy.

As I mentioned before, KEYNOTE-045 with pembrolizumab as second-line therapy showed an OS benefit compared [with] chemotherapy, with a hazard ratio of 0.73 [95% CI, 0.59-0.91; P = .002], and that’s statistically significant.

All the other second-line checkpoint inhibitors have a trend toward OS, especially [if the tumors being treated are] PD-L1 positive.

What do the National Comprehensive Cancer Network (NCCN) guidelines in bladder cancer recommend?

The NCCN guidelines for platinum-refractory, second-line therapy show that pembrolizumab is the preferred category 1 agent, based on phase 3 data for OS.7 However, the other 4 checkpoint inhibitors can be considered as well, along with erdafitinib [Balversa], which is an FGFR inhibitor, if patients’ tumors are FGFR positive. Enfortumab vedotin-ejfv [Padcev] is also approved as subsequent-line therapy after immunotherapy.

As I mentioned before, KEYNOTE-045 with pembrolizumab as second-line therapy showed an OS benefit compared [with] chemotherapy, with a hazard ratio of 0.73 [95% CI, 0.59-0.91; P = .002], and that’s statistically significant.

All the other second-line checkpoint inhibitors have a trend toward OS, especially [if the tumors being treated are] PD-L1 positive.

What is the recommendation for this patient now that he has developed pneumonitis?

The NCCN guidelines for pneumonitis [indicate that] for grade 1, you want to consider holding immunotherapy and reassess in 1 to 2 weeks. If [patients] don’t improve, you can consider a CT scan with contrast. For moderate grade 2 pneumonitis, you want to hold immunotherapy. Consider [a] pulmonary consult early, as well as [doing] a thorough infectious work-up and consider enteric antibiotics if the infection is not fully ruled out. Then, you want to start high-dose steroids and close monitoring every 3 to 7 days. If there’s no improvement after 48 to 72 hours with high-dose steroids, then you would treat it as grade 3.

For severe grade 3/4 pneumonitis, you definitely want to permanently discontinue immunotherapy and consider admitting the patient to the hospital with a full infectious work-up and pulmonary work-up. You may want to consider [getting a bronchoscopy] and continuing high-dose steroids. If there’s no improvement after 48 hours, then you would consider infliximab, intravenous immunoglobulin, or mycophenolate. I want to emphasize that this needs to be a multidisciplinary team effort, as these patients with severe pneumonitis can decompensate rapidly. You want to get everyone involved.

How do you define pneumonitis grades 1 through 4? Is it radiographic, or is it also clinical?

It’s mostly clinical. It’s basically mild, moderate, and severe. I would say [in this case] it’s more clinical, based on [the patient’s] symptoms.

What third-line options would you consider if this patient’s disease progresses?

Enfortumab vedotin is an effective drug; it is an antibody-drug conjugate to Nectin-4, which is expressed in over 90% of urothelial cancer cells. This has also been recently approved after immunotherapy with a high response rate,8 including a 38% response rate in [patients with liver metastases].9 If patients have an FGFR alteration, we can consider erdafitinib.

Other agents to look out for include sacituzumab govitecan [Trodelvy], an antibody-drug conjugate to TROP-2 that’s also expressed in urothelial cancer.

_References:

_{1. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA. July 5, 2018. Accessed August 26, 2020. https://bit.ly/3lta1oz}

_{2. 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. doi:10.1016/S0140-6736(17)33297-X}

_{3. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322. doi:10.1016/S1470-2045(17)30065-7}

_{4. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411. doi:10.1001/jamaoncol.2017.2411}

_{5. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64. doi:10.1016/ S1470-2045(17)30900-2}

_{6. 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}

_{7. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed August 26, 2020. https://bit.ly/3lold5s}

_{8. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA. December 19, 2019. Accessed August 26, 2020. https://bit.ly/3lnbLiQ}

_{9. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37(29):2592-2600. doi:10.1200}