Gaining Ground With Immunotherapy in Genitourinary Malignancies

Bradley A. McGregor, MD

Immunotherapy, in the right setting, plays a central role in the management of patients with genitourinary malignancies (GU), as evidenced by data from the phase 3 JAVELIN Bladder 100 trial, explained Bradley McGregor, MD.

In the phase 3 study, the addition of avelumab (Bavencio) to best supportive care (BSC) led to a median overall survival (OS) of 21.4 months versus 14.3 months with BSC alone in patients with locally advanced or metastatic urothelial carcinoma (HR, 0.69; 95% CI, 0.56-0.86; P <.001). The survival benefit with avelumab extended across all prespecified subgroups, including those who received cisplatin-based or carboplatin-based chemotherapy, and regardless of whether response or stable disease was reached after first-line induction chemotherapy.¹

“We’ve seen the combination of chemotherapy and atezolizumab (Tecentriq) in the frontline setting, which showed a very small benefit. We’ve also seen the press release for the combination of chemotherapy plus pembrolizumab (Keytruda), which did not meet its coprimary end points. Therefore, to have this data [from JAVELIN Bladder 100] is quite remarkable,” said McGregor.

On June 30, 2020, the FDA approved avelumab as maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy, according to the JAVELIN Bladder 100 findings.²

Research regarding the optimal role of immunotherapy in metastatic renal cell carcinoma (mRCC) has also become apparent with studies, such as HCRN GU16-260 and OMNIVORE, which are evaluating nivolumab (Opdivo) followed by salvage immunotherapy.

“In RCC, multiple perioperative trials are ongoing with immunotherapy. There’s also the PROSPER RCC trial, which is currently enrolling patients, as well as trials looking at adjuvant pembrolizumab (Keytruda), atezolizumab, nivolumab/ipilimumab (Yervoy), and nivolumab alone,” said McGregor.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Genitourinary Malignancies, McGregor, clinical director, Lank Center for Genitourinary Oncology, senior physician, Dana-Farber Cancer Institute, and instructor of medicine, Harvard Medical School, discussed some of the recent approaches that have emerged in bladder cancer and RCC, as well as anticipated developments in each field.

OncLive®: Could you highlight key updates in bladder cancer from the 2020 ASCO Virtual Scientific Program?

McGregor: The most practice-changing abstract across GU malignancies was in bladder cancer. For the first time in bladder cancer, we had a session in the plenary session with the JAVELIN Bladder 100 trial. In the trial, patients who did not progress on platinum-based chemotherapy were randomized to best supportive care versus avelumab.

Right now, the standard of care is 4 to 6 cycles of chemotherapy followed by a treatment break, and then you pursue immunotherapy upon progression. [JAVELIN Bladder 100] was unique in that the investigators moved that starting point of avelumab from progression to within 4 weeks or so of completing chemotherapy.

The investigators reported a remarkable improvement in OS of about 7 months with avelumab in patients who had stable disease or any response to platinum-based chemotherapy. This is really practice changing.

It’s really interesting to look at this in the context of the combination trials. It really represents a new standard of care. In my practice, now, I am pursuing avelumab for those patients who do not progress on 4 to 6 cycles of platinum-based therapy.

What are your thoughts on the IMvigor010 trial?

This was also a very interesting trial. The trial wasn’t practice-changing because it wasn’t [compared with the] standard care. We know immunotherapy certainly has a role in bladder cancer. There is certainly activity in it. We know [there are certain situations where] the risk of relapse is high in patients who undergo cystectomy. Can we do something more in that situation? Can we take the activity of immunotherapy in the metastatic setting and move that activity into the adjuvant setting to make a difference?

In this trial, patients who had undergone cystectomy for aggressive bladder cancer, with or without chemotherapy, and patients were randomized to observation or adjuvant atezolizumab for 1 year. Despite looking at very high-risk patients, nearly half of patients were node positive, we didn’t see any improvement in disease-free survival or OS.

We were very excited about this potential, and it’s a little disheartening to see a negative trial. However, we’ll look for more data. There’s the ongoing AMBASSADOR trial with pembrolizumab in the same space. We’re continuing to study immunotherapy in the operative and perioperative settings in other GU malignancies.

What are some emerging approaches that you’re excited about?

In urothelial cancer, the JAVELIN Bladder 100 data are fantastic, but what we would really like to do is prevent patients from getting to that point and improve the chance of curing patients with localized disease. We’re looking at harnessing all of these new drugs that we have in the metastatic space and using them earlier. Ongoing trials are looking at FGFR inhibition in the adjuvant space, potentially using drugs like enfortumab vedotin (Padcev), which is very active in the perioperative space, or even in the first-line metastatic setting. After years of negative trials, now in the past couple years, 5 different checkpoint inhibitors have been approved. Erdafitinib (Balversa) was approved for patients with FGFR mutations, enfortumab was approved following platinum-based therapy and immunotherapy, for all patients with an impressive response rate.

Now, we’re looking at combinations of these drugs and moving them early into the disease course. In addition, we are looking at new targets and drugs like sacituzumab govitecan which is another antibody-drug conjugate with a different target and toxicity profile. Ongoing trials are looking at VEGF inhibition. Some data with cabozantinib (Cabometyx) and atezolizumab was presented at the 2020 ASCO Virtual Scientific Program.

It’s really an exciting time. As we make headway in the metastatic space, the hope is that we can take those advances and move them into that perioperative space.

Shifting to mRCC, what are some of the key data that read out recently in the frontline setting?

In the frontline setting, we have been spoiled in RCC. It seems like a new phase 3 trial is presented at every [medical] meeting. At the 2020 ASCO Virtual Scientific Program, we did see the updated analysis of pembrolizumab plus axitinib (Inlyta) versus sunitinib (Sutent). With extended follow-up, we saw that the OS benefit persisted and the complete response (CR) rate increased a little bit with the combination, continuing to show that this is a very active regimen in RCC.

What are your thoughts on the HCRN GU16-260 trial?

There is that trial, and there’s also the OMNIVORE trial. At the 2017 ESMO Congress, data on the combination of nivolumab and ipilimumab were initially presented. The combination shows fantastic data, 40% response rate and 10% CR rate, but does everyone need ipilimumab? Do we need to add that extra toxicity? A total of 30% of patients were on high-dose steroids, and 60% required some sort of steroids.

An ongoing phase 2 trial is looking at nivolumab versus nivolumab plus ipilimumab, but there have been these adaptive trials. The first trial, TITAN RCC, was presented at the 2019 ESMO Congress. At the 2020 ASCO Virtual Scientific Program, the HCRN and OMNIVORE trials were presented, looking at different approaches, but essentially starting with nivolumab and then trying to salvage patients with ipilimumab. The data are very intriguing, but I don’t think [the approach] can be recommended at this point in time. There really does seem to be a benefit to using up-front ipilimumab from what we know right now. The phase 2 trial will answer that question definitively, so we look forward to those results.

Where should future research efforts be focused?

If we look at frontline mRCC, we have dual immunotherapy with nivolumab and ipilimumab and we have immunotherapy and TKIs with pembrolizumab and axitinib and avelumab and axitinib. Axitinib/avelumab probably has a very favorable toxicity profile, but no OS benefit.

Recently, we saw the press release that announced cabozantinib and nivolumab led to an improvement in OS and PFS. We’re going to have lots of options. How do you choose between immunotherapy/TKI versus dual immunotherapy? For patients who are ineligible for immunotherapy, you could think about cabozantinib or sunitinib. Then, you can say that dual immunotherapy is great, why not use all 3 agent? We have the ongoing COSMIC-313 trial, which is looking at nivolumab plus ipilimumab versus nivolumab, ipilimumab, and cabozantinib.

Our efforts are always focused on trying to improve outcomes for patients. We’re always looking for new targets and new approaches that we test in the metastatic setting first. As we find new targets, we look at [how we can use these agents] in earlier stages of disease to prevent the progression to metastatic disease.

There’s also a need for new targets. Some of the interesting data presented at the Virtual Scientific Program is looking at new targets. In RCC, these combinations are great, but there are still patients where progressive disease is their best response. Data on HIF2 inhibitors in patients with Von Hippel-Lindau syndrome-associated RCC showed impressive response rates. We look forward to the phase 2 trial of the HIF2 inhibitor versus everolimus (Afinitor), which is currently ongoing, looking for these novel targets to try to help those patients who may not respond to the best we have right now.

What is your take-home message regarding the progress that has been made in GU malignancies?

We’re finding new pathways, new targets, and looking to combine those pathways and targets to improve outcomes. In RCC, we had nothing until the advent of TKIs. Then, we had cabozantinib which showed survival benefit in the second-line setting. Then, nivolumab showed up. Now we have 3 different combinations, which improve OS in the frontline setting versus TKI monotherapy. We have all these new options that we’re looking to build on.

In bladder cancer, there was a string of negative trials. Now we have all these new agents. We’re looking at how we can use them effectively, earlier, and in combination to help our patients.

References

1. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1
2. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News release. Pfizer. June 30, 2020. Accessed August 19, 2020. bit.ly/2YO7gVk