Immunotherapy Combinations Contribute to Efficacy and Safety Advances in Genitourinary Cancer Treatment

Article

New treatment strategies with immunotherapeutic agents are challenging standards of care and prolonging survival in first and later lines of metastatic urothelial carcinoma, metastatic renal cell carcinoma, and metastatic castration-resistant prostate cancer.

Bruno R. Bastos, MD

Bruno R. Bastos, MD

New treatment strategies with immunotherapeutic agents are challenging standards of care and prolonging survival in first and later lines of metastatic urothelial carcinoma, metastatic renal cell carcinoma (mRCC), and metastatic castration-resistant prostate cancer (mCRPC), according to faculty from an OncLive® State of the Science SummitTM on genitourinary cancer.

The event, chaired by Bruno R. Bastos, MD, a medical oncologist at the Miami Cancer Institute at Baptist Health South Florida, focused on leveraging avelumab (Bavencio) maintenance therapy and novel combination regimens in urothelial carcinoma, emerging treatments in patients with mRCC who have previously received immunotherapy agents, and the role of PARP inhibitors in mCRPC.

Bastos was joined by his colleagues:

  • Kristen Millado, MD, medical oncologist, hematologist, the Miami Cancer Institute at Baptist Health South Florida
  • Maria Carla Dominguez, MD, medical oncologist, the Miami Cancer Institute at Baptist Health South Florida
  • Antonio Muina, MD, medical oncologist, hematologist, the Miami Cancer Institute at Baptist Health South Florida

Below, Bastos, Millado, Dominguez, and Muina summarize the main messages from their presentations.

Frontline Treatment of Metastatic Urothelial Carcinoma: A Practice-Changing Maintenance Strategy

Millado: [I spoke about the phase 3] JAVELIN Bladder 100 trial [NCT02603432], which showed that patients with advanced urothelial carcinoma who responded or had stable disease after the first line of platinum chemotherapy had prolonged overall survival [OS] with maintenance avelumab compared with best supportive care alone. This was true in both in the overall population and in the PD-L1–positive population.

Platinum-based chemotherapy is great at getting control of disease, but often, that control does not last very long. In contrast, immunotherapies, especially in urothelial carcinoma, are not great at getting fast control of disease. However, [when patients do respond to these treatments,] they often [experience] durable responses.

OS was longer in the avelumab group, despite more frequent use of subsequent treatment in the control group, which highlights the benefit of using avelumab as maintenance therapy rather than waiting for disease progression. Historically, only a minority of [patients with] bladder cancer who are diagnosed receive second-line therapy. At that point, typically, the cancer is growing back fast.

The safety profile of avelumab was manageable, with relatively low rates of grade 3 or greater adverse effects [AEs]. No new safety signals were identified. Now, avelumab maintenance therapy represents a new standard of care, and we have evidence to support its clinical use. On June 30, 2020, the FDA approved avelumab maintenance for patients with locally advanced metastatic urothelial carcinoma that has not progressed on first-line platinum-based chemotherapy.

[I concluded with] some thoughts about future directions. The clinical usefulness of PD-L1 as a biomarker in advanced urothelial carcinoma is still an area of uncertainty; PD-L1 is an imperfect biomarker. We need future biomarker development to include composite biomarker panels, which will help refine and identify subgroups of patients with differences in clinical benefit. There is also still an unmet need when it comes to characterizing patients with rapidly progressing disease on first-line chemotherapy, as these patients may also be refractory to immunotherapy and were not included in the study.

Lastly, exploring the role of immune checkpoint inhibitors in combination with other targeted agents and antibody-drug conjugates in advanced urothelial carcinoma is an exciting topic. Several phase 3 trials are presently underway. As of June 2022, we have preliminary data from the phase 3 DANUBE [NCT02516241], KEYNOTE-361 [NCT02853305], and CheckMate 901 [NCT03036098] trials. Unfortunately, these early data do not show an improvement in benefit over first-line platinum-based therapy with durvalumab [Imfinzi], tremelimumab, or ipilimumab [Yervoy] plus nivolumab [Opdivo] compared with cisplatin-based chemotherapy or with pembrolizumab [Keytruda] plus platinum-based chemotherapy compared with platinum-based chemotherapy alone.

We are highly anticipating the results of the [phase 3] NILE [NCT03682068], LEAP-011 [NCT03898180], and EV-302 [NCT04223856] trials. Hopefully, [data from] those [trials] are positive.

Many advancements [have been made] in urothelial carcinoma up front and in the advanced setting, especially in the past 5 years. I am excited that we are moving in the direction of potential personalized combination therapies. We have a variety of treatment options to offer patients now, and most importantly, these interventions are improving OS in our patients.

Later-Line Treatment of Metastatic Urothelial Cancer

Dominguez: [I discussed the phase 1b COSMIC-021 trial (NCT03170960) cohort 2 expansion] in patients with urothelial carcinoma who were previously treated with platinum-based chemotherapy. Cabozantinib [Cabometyx] plus atezolizumab [Tecentriq] produced durable responses with acceptable toxicity. The overall response rate [ORR] was 27%, the median duration of response [DOR] was not reached [NR], and the longest ongoing response was 15.6 months.

Evaluation of cabozantinib and atezolizumab in other urothelial carcinoma cohorts is still ongoing, including in cisplatin-ineligible patients without previous systemic therapy, in cisplatin-eligible patients without prior systemic therapy, and those previously treated with immune checkpoint inhibitors.

[I also discussed] cohort 3 of the phase 2 TROPHY-U-01 trial [NCT03547973]. [In this cohort, the] combination of sacituzumab govitecan-hziy [Trodelvy] and pembrolizumab was associated with an ORR of 34% in patients with metastatic urothelial cancer after progression [on platinum-based chemotherapy]. This study met its objective, with more than 13 responses observed.

After a median follow-up of 5.8 months, the median DOR and the median OS were NR, and the safety profile was manageable. No new safety signals were observed, and there was no increased rate of immune-related AEs. Follow-up [studies of] biomarkers are still ongoing. The results from this trial support further studies combining sacituzumab govitecan with checkpoint inhibitors in earlier lines of therapy or after platinum-based chemotherapy. Additional combination regimens of sacituzumab govitecan are under evaluation in other cohorts of this study, and in the phase 3 TROPiCS 04 trial [NCT04527991].

Frontline Therapy in mRCC

Bastos: [The first trial I discussed was] the phase 3 KEYNOTE-426 trial [NCT02853331], which studied pembrolizumab, [an immunotherapy], plus axitinib [(Inlyta), a TKI], vs sunitinib [(Sutent), another TKI]. This trial showed a 12-month OS [rate] of 90% with pembrolizumab plus axitinib vs 79% with sunitinib. At 24 months, 74% and 66% [of patients were alive in the pembrolizumab and sunitinib arms, respectively]. The response rate was 60% with pembrolizumab plus axitinib vs 39% with sunitinib. Immunotherapy plus the TKI elicited a better response than the TKI alone in this setting. [The median DOR] was 23.5 months with the combination vs 15.9 months with the TKI alone. Pembrolizumab plus axitinib is approved [in this setting].

The second trial I discussed was the phase 3 CheckMate 9ER study [NCT03141177], which looked at nivolumab plus cabozantinib vs sunitinib, [another trial comparing an] immunotherapy plus a TKI vs another TKI. This trial led to the approval of [nivolumab plus cabozantinib in this setting]. The OS [rate] with the combination was 70% at 24 months vs 60% with sunitinib alone.

The third trial I discussed, [which] also [investigated an] immunotherapy [in combination with] a TKI, was the [phase 3] CLEAR trial [NCT02811861], [which evaluated] lenvatinib [Lenvima] plus pembrolizumab or everolimus [Afinitor] vs sunitinib in advanced RCC. The lenvatinib plus pembrolizumab regimen showed benefit in almost all subgroups. The poor-risk subgroup benefitted the most from the combination. The only subgroup that did not benefit from the combination was the favorable-risk subgroup. Nevertheless, this combination is approved for poor-risk, intermediate-risk, and favorable-risk patients.

All 3 immunotherapy/TKI combinations do not seem to have as great a benefit in the favorable-risk subgroups as they do in the poor- and intermediate-risk subgroups.

Two other ongoing trials [are investigating only the intermediate- and poor-risk subgroups]. One is the phase 3 CheckMate 214 trial [NCT02231749], which is comparing [the dual immunotherapy combination of nivolumab and ipilimumab] vs sunitinib. The 5-year OS rate is 48% for the combination vs 37% for sunitinib. A total of 43% of [the patients in the combination arm] are alive after 5 years with stage IV disease vs 31% [in the sunitinib arm]. In terms of the favorable-risk subgroup, sunitinib was always [leading] in this trial. However, now, at 5 years, it is changing; the sunitinib rates are going down and the [combination rates are remaining consistent]. Nivolumab plus ipilimumab is still not approved [for use] in the favorable-risk subgroup, but these data may support the use of an immunotherapy combination in the first line in this population.

I also talked about the [phase 2] CABOSUN trial [NCT01835158], which compared cabozantinib with sunitinib in previously untreated patients with RCC with poor- or intermediate-risk disease. This trial indicates the possibility that a TKI [can treat this disease] more effectively [than the treatments we already have].

Second-Line and Later-Line Treatment of mRCC

Bastos: [I presented the] OS data from the phase 3 METEOR trial [NCT01865747], which looked at cabozantinib plus everolimus. These data are the reason why cabozantinib is used in the second line. Five percent of patients had received previous therapy with an immune checkpoint inhibitor. The ORR was 17% in the cabozantinib arm vs 3% in the everolimus arm, indicating that cabozantinib has activity post-TKI treatment. [Data about post-immunotherapy survival in the second line] are most relevant to our current practice.

[I also talked about] the [phase 3] AXIS trial [NCT00678392], because it studied axitinib. [Here,] axitinib [was compared] with sorafenib [Nexavar] in patients who had progressed on sunitinib, bevacizumab [Avastin] with interferon alfa, [cytokine therapy, or temsirolimus (Torisel)]. Axitinib is approved [in this setting], but there are no immunotherapy data.

I also discussed data with nivolumab in the second line. We used to frequently use nivolumab as a second-line therapy after sunitinib and VEGF TKIs. Some people still use that approach, but it is not what most practices are doing right now. However, the [phase 3] CheckMate 025 trial [NCT01668784] evaluated nivolumab vs everolimus in patients who had received 1 or 2 prior TKIs.

I also presented on 2 trials that have more real-world practice data from patients who had previously received 2 lines of treatment with immunotherapy and a TKI. [The phase 1/2 KEYNOTE-146 trial (NCT02501096)] looked at lenvatinib plus pembrolizumab. Here, the ORR in patients who were immunotherapy naïve was 41% compared with 55% in [patients who had received previous immunotherapy].

The phase 3 TIVO-3 trial [NCT02627963] showed more real-world data [reflective of] what we do in practice. [This trial included] patients who [received] prior TKI treatment, and prior immunotherapy was allowed. This trial compared tivozanib [Fotivda], a VEGF TKI, with sorafenib. At 6 months, the progression-free survival [PFS] rate, which was the primary end point, was 49.6% with tivozanib vs 35.1% with sorafenib. At 12 months, the PFS rate was 31.2% vs 18.4% in the tivozanib and sorafenib arms, respectively. At 48 months, the PFS rate was 7.6% in the tivozanib arm compared with 0% in the sorafenib arm.

We want to see more data with patients who received prior immunotherapy. Tivozanib is approved because of these data, and there are opportunities to move immunotherapies to other combinations, such as an immunotherapy and TKI combination in the first line, to provide better responses than what we currently [achieve].

PARP Inhibitors in Prostate Cancer

Muina: In the multicohort, phase 3 MAGNITUDE trial [NCT03748641] the addition of niraparib [Zejula] to first-line abiraterone acetate [Zytiga] plus prednisone prolonged radiographic PFS [rPFS] vs placebo and abiraterone acetate plus prednisone in patients with mCRPC and homologous recombination repair [HRR] gene alterations.

The risk of progression or death was significantly reduced by 48% in the BRCA1 and BRCA2 subgroups, as well as by 27% in all other biomarker groups. A prespecified futility analysis found no benefit with the addition of niraparib to abiraterone acetate plus prednisone in patients who were biomarker negative. The independent data safety monitoring committee stopped enrollment to this cohort for this reason.

Niraparib plus abiraterone acetate and prednisone improved other clinical outcomes vs placebo plus abiraterone acetate and prednisone in the biomarker-positive cohort. Time to cytotoxic chemotherapy, time to symptomatic progression, time to prostate-specific antigen progression and ORRs were improved in the niraparib arm compared with the placebo arm. Quality of life was maintained in the niraparib arm in the biomarker-positive group. No new safety signals were identified. These findings support the use of niraparib plus abiraterone acetate and prednisone as a first-line treatment option for patients with mCRPC and HRR gene alterations, underscoring the need to test for gene alterations in this patient population.

In the MAGNITUDE trial, all patients were pre-tested, and investigators knew the patient biomarkers prior to trial enrollment. In the [phase 3] PROpel trial [NCT03732820], however, that was not the case. The addition of olaparib [Lynparza] to first-line abiraterone acetate plus prednisone significantly prolonged rPFS vs placebo and abiraterone acetate plus prednisone in patients with mCRPC. The median rPFS per investigator assessment was 24.8 months in the olaparib arm vs 16.6 months in the placebo arm. An rPFS benefit was observed across all prespecified subgroups, including biomarker-positive and biomarker-negative or biomarker-unknown groups. The safety profile was consistent with established profiles for each group. Olaparib and abiraterone acetate plus prednisone was the first combination regimen to demonstrate a clinical benefit in first-line mCRPC, regardless of biomarker status. [This study showed] that you can give this regimen to all patients. Olaparib plus abiraterone acetate and prednisone has not been FDA approved yet, but [approval looks promising].

Related Videos
Nikhil A. Gopal, MD
Nikhil A. Gopal, MD
Jaime R. Merchán, MD, Sylvester Comprehensive Cancer Center
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
A panel of 5 experts on renal cell carcinoma
A panel of 5 experts on renal cell carcinoma
Brian I. Rini, MD, FASCO
Kathryn Beckermann, MD, PhD
Eleonora Dondossola, PhD