The focus of new trials has been on the combination of PD-1 inhibitors with other systemic agents. The combination of chemotherapy with PD-1 agents has gain significant interest due to the possible immune priming effect that chemotherapy may have by the release of tumor neo-antigens. Presently, three trials are enrolling patients in the first line setting, CheckMate-901 (Nivolumab /Ipilimumab + Gem-Cis), Keynote 361 (Pembrolizumab + Platinum chemotherapy), ImVigor 130 (Atezolizumab + platinum based chemotherapy) and Danube trial (Durvalumab With or Without versus Tremelimumab Platinum chemotherapy). At this time it is unclear which agent should be given first, there are theories supporting the use of immunotherapy first followed by chemo while others support the use of chemo first. An important trial being done at MSCKCC is attempting to answer this question performing tumor biopsies in between treatment agents. In addition to assessing the timing of each agent the investigators are hoping that the tumor biopsies will also shed some light in to possible pathways for treatment resistance.
Preliminary studies have shown a possible advantage of using anti-angiogenic therapies for the treatment of bladder cancer. The combination VEGF inhibitors with immunotherapy agents has gain some popularity after the discovery of myeloid suppressive cells that seem to have a detrimental effect on immunotherapy response. The theory behind using anti-VEGF therapies is to decrease the blood supply to the tumor in order to decrease the infiltration of myeloid suppressive. One trial is currently assessing the benefit of adding bevacizumab to atezolizumab in patients who have failed platinum based chemotherapy.
The results of CheckMate 032, which showed a significant improvement using a combination of CTLA4 (ipilimumab) and PD-1 (nivolumab) inhibitors in small-cell lung cancer has open the door to trials in bladder cancer. The trial did report an increase rate of side effects associated with the combination which have caused some concern given the older and more friable population seen in bladder cancer. Combination of PD-1 agents with IDO inhibitors have also shown some promise. The IDO protein, or indoleamine (2,3)-dioxygenase, has been identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. The dual check-point blockade was studied in a phase I study assessing the combination of pembrolizumab with epacadostat, which showed a response rate of 35% with no increases in adverse events.
The use of immunotherapy has also been introduced in the adjuvant setting with three trials currently enrolling patients: CheckMate 274 (Nivolumab), IMVigor 201 (Atezolizumab) and AO21501 (Pembrolizumab). Two trials (SWOG 1606 and Keynote 057) are currently enrolling for patients with BCG refractory disease who are interested in bladder preservation. The results of this trials will be awaited with significant excitement since a positive result in the adjuvant or BCG refractory setting will create significant shifts in the management of bladder cancer patients.
In summary, multiple immunotherapy combinations are being tested in the non-muscle invasive, muscle invasive and metastatic setting. As excitement grows with the use of immunotherapy we must also continue to evaluate factors that lead to disease sensitivity and resistance as proper patient selection remains elusive.
Presented by: Jonathan Rosenberg MD, Enno W. Ercklentz Chair in Medical Oncology at Memorial Sloan Kettering Cancer Center
Written by: Andres F. Correa, Society of Urologic Oncology Fellow, Fox Chase Cancer Center-Temple Health, Philadelphia, PA at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC