Daniel George, MD, is Professor of Medicine and Surgery and Director of Genitourinary Oncology at the Duke Cancer Institute. In the following article, he provides his perspective on new developments in the use of systemic immunotherapy.
Prior to 2016, there have been few significant new developments in the treatment of metastatic bladder cancer—and few available treatments that had the potential to change the natural course of this disease. Most patients with metastatic bladder cancer have historically been treated with cisplatin, approved by the FDA in 1978, or non-platinum chemotherapy. Yet in the past year, several checkpoint inhibitors have emerged as promising immunotherapies for the treatment of bladder cancer—particularly for advanced urothelial cancer in the second-line setting.
In February of 2016, the FDA granted breakthrough designation for durvalumab in the treatment of PD-L1 positive advanced urothelial cancer after treatment failure with platinum chemotherapy. The FDA also granted accelerated approval for atezolizumab in the post-platinum chemotherapy setting in May, 2016. Finally, the phase III KEYNOTE-045 study, testing Merck’s pembrolizumab against investigator choice of chemotherapy in previously treated advanced urothelial cancer patients, was halted early in late October since it had met its primary endpoint of overall survival (OS). Although specific results of the study have not yet been released, a press release from Merck noted that the study’s results indicated that pembrolizumab is the first immunotherapy to show improved OS compared with chemotherapy in advanced urothelial cancer. (insert Slide)
Clinical trials on these immunotherapies indicate that checkpoint inhibitors cause an anti-tumor response in locally advanced/metastatic urothelial cancer, and responses are improved over historical controls. Responses to these drugs are particularly favorable among patients with higher PD-L1 status. Responses are also durable, can last for more than a year, and patients with advanced urothelial cancer can continue to respond to checkpoint inhibitors even after disease progression. Thus, checkpoint inhibitor therapies—particularly post-chemotherapy—are likely to be powerful new tools in the treatment of advanced bladder cancer. As well as providing favorable response rates, these therapies produce toxicities that are usually manageable.
Atezolizumab is one example of a checkpoint inhibitor therapy that has clear benefits for previously treated advanced urothelial cancer patients. In the phase II IMvigor210 study, 119 patients with locally advanced or metastatic urothelial cancer—who were deemed ineligible for treatment with cisplatin chemotherapy—were treated with atezolizumab. In a second cohort or Cohort 2, 310 metastatic urothelial cancer patients who had progressed during or after treatment with platinum-based chemotherapy, were also treated with atezolizumab until the patients showed no further benefit. The accelerated FDA approval of atezolizumab for previously treated advanced urothelial cancer was based on the results of the phase II IMvigor210 study, and is contingent on the ongoing phase III study of this therapy in metastatic urothelial cancer.
In the IMvigor 210 study, patients in Cohort 2—who had an ECOG performance status of 0 or 1—showed a statistically significant improvement in objective response rate (ORR) of 16% compared to historical controls with an ORR of 10%. Seven percent of patients also experienced a complete response (CR). Although ORR and CR benefits were observed in all patient subgroups, those patients who had higher levels of PD-L1 immune expression were the most likely to respond, and had an ORR of 28%. By contrast, patients with low levels of PD-L1 immune expression showed an ORR of 9%.1
With a median follow-up of 17.5 months, many patients in Cohort 2 in the IMvigor210 study also had unusually durable responses. At the median follow-up of 17.5 months, 71% of responses were ongoing and 86% of complete responses were ongoing. The 12-month OS survival was also favorable compared to historical controls – 37% vs. 20%. In patients with higher levels of PD-L1 immune expression the OS benefit was even greater; among these patients, the 12-month overall survival was 50%.1,2
At the investigator’s discretion, patients who derived clinical benefit from atezolizumab, but showed evidence of disease progression as defined by RECIST criteria, could continue to receive treatment. Results indicated that of the 134 patients in Cohort 2 who received treatment after disease progression, 19% had SLD reductions of ≥30% in target lesions, and 28% experienced disease stabilization. The median OS for these patients was 11.4 months beyond progression, and the 12-month OS in patients treated beyond progression was 50%. Taken together, these results indicate the potential for atezolizumab to produce non-classical responses in this patient population.1
Patients with metastatic urothelial cancer have a life expectancy that is less than one year, so they may be willing to endure some considerable toxicities if the benefit of the drug is great enough. Yet, even in this population, atezolizumab was relatively well tolerated; serious adverse events affected 46% of patients. Of these adverse events, fatigue, nausea, decreased appetite and pruritus was most prevalent. Of note, immune-related adverse events were relatively infrequent, but there were many types of these toxicities, ranging from pneumonitis to dyspnea and colitis. Ten percent of immune-related adverse events required steroids, but none required immunomodulatory agents in the trial.1
The 119 patients in Cohort 1 of the trial, who were ineligible for cisplatin chemotherapy, also received significant benefits from atezolizumab treatment. In these patients, the ORR was 24% and the CR rate was 7%. As in the previously treated patients enrolled in Cohort 2, the ORR was higher among those with higher levels of PD-L1 immune expression than among those with low or no expression of PD-L1 (28% vs. 21%-23%).3
Yet why wasn’t atezolizumab approved for first-line cisplatin ineligible patients? The answer is that while atezolizumab produced favorable outcomes in this population, these patients also have other reasonable treatment options. By contrast, patients with platinum-refractory advanced urothelial cancer have no good standard treatment choices.1,4
There are now ongoing clinical trials testing immunotherapies in the post-cystectomy setting, in first line metastatic urothelial cancer and in high risk non-muscle invasive bladder cancer. These clinical trials are researching immunotherapies such as atezolizumab, pembrolizumab, nivolumab and durvalumab—either as single agents or in combination with chemotherapy or another checkpoint inhibitor, such as tremelimumab.
In the next few years, research efforts will continue to highlight advances in immunotherapy treatment of bladder cancer. The effective use of checkpoint inhibitors for bladder cancer constitutes the most sweeping change in management of this cancer since the advent of platinum-based chemotherapy. Although single checkpoint inhibitors have activity in the setting of advanced bladder cancer, immunotherapy treatment in this setting will likely shift toward a preference for combination therapies, due to their enhanced efficacy.
Urologists should expect to see durable responses in bladder cancer patients treated with checkpoint inhibitors—much more durable than with chemotherapies. However, the threat of toxicities with these agents—especially when used in combination—is very real. As we begin to increasingly use immunotherapies in bladder cancer, we will also need to collaborate more with other oncology disciplines to manage treatment-related complications.
Written by: Daniel George, MD
1. Dreicer R. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol. 2016; 34 (Suppl 2S, abstract 355.)
2. Agarwal N, Bellmunt J, Maughan BL, et al. Six-month progression-free survival as the primary endpoint to evaluate the activity of new agents as second-line therapy for advanced urothelial carcinoma. Clin Genitorurin Cancer. 2014; 12 (2): 130-7.
3. Balar A. Atezolizumab (atezo) as first-line (1L) in cisplatin ineligible locally advanced/metastatic urothelial cancer (mUC): Primary analysis of IMvigor210 cohort 1. J Clin Oncol. 2016; 34 (Suppl; abstract LBA4500).
4. De Santis M, 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.
5. Bellmunt J, et al. KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer. J Clin Oncol. 2015; 33 (Suppl, Abstract TPS4571).