Immune System Agents May Move Into Earlier Settings in GU Cancers

Randy F. Sweis, MD

Over the past 5 years, medical oncologists have witnessed the revolutionary impact of immunotherapy on patients with advanced urologic malignancies. Over the next 5 years, these therapies likely will similarly transform urologic surgical care. In the metastatic setting, the 2-year frontline progression-free survival rate for high-risk clear cell renal carcinoma has nearly doubled, from 17% with sunitinib (Sutent) to 30% with combination immunotherapy of ipilimumab (Yervoy) plus nivolumab (Opdivo).¹ Overall survival (OS) at 2 years in the same study was 66% with immunotherapy compared with 53% for sunitinib. In refractory prostate cancer, the same combination, although given at different doses, was shown to have an objective response rate of 26% in docetaxel-naïve patients.² In bladder cancer, multiple immunotherapy drugs have received FDA approval since 2016, and median OS was prolonged with pembrolizumab (Keytruda) immunotherapy to 10.3 months versus 7.4 months with chemotherapy.³ These therapies have led to long-term survival for many patients in the metastatic setting, for which the outlook has been historically poor. A logical extension of these clinical research efforts has been to insert immunotherapy earlier into the course of disease, including in the perioperative setting.

Early-stage bladder cancer is one of the most active areas of immunotherapy investigation. Recurrences of nonmuscle invasive bladder cancer (NMIBC) can be prevented with bacille Calmette-Guérin (BCG) immunotherapy, which clinicians have used for over 40 years. Yet up to 50% of patients either fail to respond or relapse within the first 5 years of treatment. Evidence of PD-L1 upregulation in the tumor microenvironment after BCG therapy has now been reported,⁴ and the exploration of PD-1 immune checkpoint blockade in early-stage tumors is under way. Additionally, investigators are evaluating the IDO inhibitor BMS-986205 in combination with nivolumab anti—PD-1 therapy in BCG-unresponsive NMIBC (NCT03519256). Prevention of recurrences or progressions could ultimately reduce the number of patients who develop muscle-invasive or metastatic urothelial cancer.

Table. Select Trials of Immuno-Oncology Agents in Urological Cancers (^1-3,5,9)

For patients with localized urothelial cancer (T2-T4 disease), outcomes remain poor despite optimal neoadjuvant chemotherapy and surgery. In this setting, adjuvant studies with several anti—PD-1/PD-L1 antibody therapies are in progress for cisplatin-ineligible patients or patients with residual disease after neoadjuvant chemotherapy. Similarly, neoadjuvant immunotherapy studies are investigating anti–PD-1/PD-L1 therapy both alone and in combination with chemotherapy. Preliminary data from the PURE-01 and ABACUS studies indicated that pathologic complete response to pembrolizumab and atezolizumab (Tecentriq) was 42.0% and 29.0%, respectively.^5,6 These same antibodies are being investigated in 2 large, randomized, phase III, 3-arm studies that include chemotherapy, combination chemotherapy and immunotherapy, and immunotherapy alone. These approaches could ultimately transform the prognosis for patients with newly diagnosed T2 and higher localized bladder cancer. In renal cancer, investigators are studying both adjuvant and neoadjuvant approaches. Adjuvant trials with atezolizumab, pembrolizumab, durvalumab (Imfinzi), and nivolumab with or without ipilimumab are accruing. Additionally, the perioperative PROSPER RCC trial is under way via cooperative groups to study nivolumab therapy both prior to and after nephrectomy. Investigators have hypothesized that starting immunotherapy treatment with the tumor intact can enhance antigen-specific T-cell reactivation compared with using therapy only postoperatively. Additionally, neoadjuvant therapy can lead to dramatic responses in patients with initially unresectable disease and can enable curative surgery.⁷ In the perioperative setting, the tyrosine kinase inhibitor therapies were largely unable to improve outcomes, with the controversial exception of sunitinib, which was approved for renal cancer in the adjuvant setting. Nonetheless, given its very different mode of action, anti—PD-1/PD-L1 immune checkpoint therapy has the potential to shift the paradigm of treatment in localized renal cancer.

Beyond sipuleucel-T (Provenge), immunotherapy in prostate cancer has been a challenge, but signs of hope are emerging. Investigators evaluated neoadjuvant ipilimumab with androgen-deprivation therapy in prostate cancer, and clinical or pathologic complete responses were not observed.⁸ However, upregulation of PD-L1 and VISTA inhibitory molecules on macrophages in treated tumors was observed as a potential mechanism of resistance. Results of a more recent study of combination ipilimumab and nivolumab in patients with metastatic prostate cancer have shown response rates of 25% in chemotherapy-naïve patients and 10% in patients with prior taxane therapy.⁹ Importantly, response rates were better in the chemotherapy-naïve cohort, whose patients are generally earlier in the disease course, when tumors are less refractory. This trend may support further investigation of combination immunotherapies at even earlier stages of prostate cancer, such as the perioperative setting. Indeed, some trials are even targeting the active surveillance population. One such trial involves administration of an adenoviral vector expressing the herpes simplex virus thymidine kinase gene concomitantly with the prodrug valacyclovir (Valtrex). This combination leads to tumor cell death and is intended to generate a tumor-specific in situ vaccination (NCT02768363). Preventing the development of advanced, invasive prostate cancer at a very early stage is an exciting prospect in improving outcomes in prostate cancer.

Given the shift in outcomes that urologic practices may see with immunotherapies, management of toxicities will, in parallel, become an important part of practice that clinicians could successfully manage through multidisciplinary teams or ongoing partnerships with medical oncologists and other specialists, such as gastroenterologists and rheumatologists. Clinical data indicate that immunotherapy given earlier in the disease course has the potential to have even higher efficacy than in the refractory metastatic setting. Thus, the promise of immunotherapy to transform care for patients with genitourinary cancer may be greatest in urologic care when cure is most attainable (Table ^1-3,5,9).

References

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7. Labbate C, Hatogai K, Werntz R, et al. Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy. J Immunother Cancer. 2019;7(1):66. doi: 10.1186/s40425-019-0546-8.
8. Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23(5):551-555. doi: 10.1038/nm.4308.
9. harma P, Pachynski RK, Narayan V, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). Presented at: 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 142.