Immunotherapies Continue to Show Intriguing Benefit in Cisplatin-Ineligible Metastatic Urothelial Cancer

Several trials in the field of first-line metastatic urothelial cancer are testing combinations with gemcitabine/platinum-based therapy followed by maintenance avelumab (Bavencio). However, no phase 3 trials have shown that first-line pembrolizumab (Keytruda) is better than gemcitabine and platinum-based therapy followed by avelumab as maintenance, according to Guru P. Sonpavde, MD.

“Maintenance therapy with avelumab in [patients with] responding or stable disease after 4 to 6 cycles of gemcitabine/platinum therapy should be considered practice-changing,” said Sonpavde. “Where the debate arises in terms of the role of this regimen [within the] paradigm is in cisplatin-ineligible patients who are PD-L1–high. What do we do with these patients? This is a discussion to be had with the patient. This is shared decision-making and patients drive [the decision] based on the information they receive.”

In June 2020, the FDA approved avelumab as a maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma that has not progressed with frontline platinum-based chemotherapy. The decision was based on results from the phase 3 JAVELIN Bladder 100 study, which evaluated avelumab plus best supportive care (BSC) as a first-line maintenance therapy versus BSC alone in this patient population.

After a median follow-up of 19.6 months in the avelumab arm and 19.2 months in the BSC arm, the median overall survival (OS) with the addition of avelumab versus BSC alone was 21.4 months and 14.3 months, respectively (HR, 0.69; 95% CI, 0.56-0.86; P <.001).

In an interview with OncLive® during an International Perspectives on Cancer webinar on Genitourinary Cancers, Sonpavde, the director of the Bladder Cancer Program and a physician at Dana-Farber Cancer Institute, discussed trials of interest for both cisplatin-eligible and -ineligible patients with metastatic urothelial cancer, as well as other agents coming down the pipeline.

OncLive®: Could you discuss frontline treatment strategies for patients with metastatic urothelial cancer?

Sonpavde: In the [frontline setting], we have divided these patients into cisplatin-eligible or -ineligible patients. [From there], cisplatin-eligible patients receive a regimen of gemcitabine/cisplatin or a regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen or the dose-dense regimen sometimes.

In cisplatin-ineligible patients, we have routinely given gemcitabine/carboplatin in the past; sometimes, we have done a split dose of cisplatin plus gemcitabine. This has been the standard of care. We finish with up to 6 cycles of first-line chemotherapy and then put patients on a treatment holiday. When patients progress, that is when they go on to receive second-line treatment. Of course, in the second-line setting, we have 5 PD-1/PD-L1 inhibitors approved.

The JAVELIN Bladder 100 trial has been a practice-changing trial, in which patients received 4 to 6 cycles of first-line platinum-based chemotherapy, either carboplatin/gemcitabine or cisplatin/gemcitabine. These patients, if they had stable or responding disease after 4 to 6 cycles, were randomized to switch to maintenance avelumab, a PD-L1 inhibitor, given intravenously every 2 weeks until progression or intolerable toxicities versus observation with the primary endpoint of survival.

This trial was strongly positive with a hazard ratio 0.69. The median survival improved from around 14 months to 21 months. This was a robust increment in OS, not only in the overall population, but also in the PD-L1–high population. There was an improvement in progression-free survival (PFS) in the overall population and in the PD-L1–high population, which were the dual primary end points.

This has been a practice-changing trial. Of course, in the first-line setting, we also have atezolizumab and pembrolizumab still approved in the PD-L1–high, cisplatin-ineligible group. Also, both of these agents can be used as a single-agent therapy in cisplatin-ineligible patients in the first-line space. These are patients [who are] ineligible for both cisplatin and carboplatin, regardless of PD-L1 expression.

Please discuss some additional pivotal trials in this setting. 

Four trials [to highlight] are ongoing, as opposed to already completed and reported, with both the KEYNOTE-361 trial and the DANUBE trial having been reported recently. Both of them did not change the standard of care in the first-line setting. [These trials showed that] gemcitabine/platinum plus a PD-1 inhibitor did not beat gemcitabine/platinum alone. Also, the combined checkpoint inhibitor approach with durvalumab/tremelimumab could not beat gemcitabine/platinum. Notably, durvalumab (Imfinzi) alone could not beat gemcitabine/platinum in PD-L1–high patients in the DANUBE trial.

The IMvigor130 trial in which gemcitabine/platinum plus atezolizumab did show an improvement to PFS, though we still don't have survival data yet. This is why the combination of gemcitabine/platinum plus a checkpoint inhibitor has still not emerged as a new standard of care yet. CheckMate-901 trial is a trial in the first-line disease setting. All of these trials have included patients who were either cisplatin-eligible or -ineligible. This trial primarily compares ipilimumab (Yervoy) with nivolumab versus gemcitabine/platinum and looks at survival not only in all-comers, but also in PD-L1–high patients. It also has a sub-study, which looks at cisplatin-eligible patients only with gemcitabine/platinum versus gemcitabine/platinum plus nivolumab. It will also look at the combination, although the combination of chemotherapy plus nivolumab is only being looked at in the cisplatin-eligible patients in the CheckMate-901 trial.

The second ongoing trial I want to highlight is the NILE trial. This is somewhat unique because this compares gemcitabine/cisplatin in either cisplatin-eligible or -ineligible patients and has 2 experimental groups. One is gemcitabine/platinum plus durvalumab, [and the other] experimental group is gemcitabine/platinum plus durvalumab plus tremelimumab. It's a quadruplet therapy and is an interesting and aggressive approach.

The third trial is the EV-302 trial. This is interesting because it has a standard arm of gemcitabine/platinum and 2 experimental arms. Again, this is [for] cisplatin-eligible or -ineligible [patients]. One of the experimental arms is enfortumab vedotin-ejfv (Padcev) plus pembrolizumab; the second experimental arm is enfortumab vedotin plus pembrolizumab plus platinum-based therapy—another aggressive approach. This is, of course, based on the exciting data that was seen with enfortumab vedotin plus pembrolizumab as a first-line treatment in cisplatin-ineligible metastatic patients. This was a small trial of 45 patients in which the response rate seen was 73%, so that's what inspired this phase 3 EV-302 trial.

The fourth trial is the LEAP-011 study. This is a little bit different than the 3 other trials that are ongoing because it only targets patients who are cisplatin-ineligible, PD-L1–high, or platinum-ineligible—essentially chemotherapy-ineligible. What it does is compare pembrolizumab alone with pembrolizumab plus lenvatinib (Lenvima). That has shown promising activity in mostly the salvage setting. The company is deciding to test that combination, which, as you know, the VEGF plus PD-1 combination has been promising in a lot of other cancers. For example, [this has shown to be promising in] renal cell carcinoma and now hepatocellular cancer. This approach might also be interesting in urothelial carcinoma, and so it's being examined in this frontline phase 3 trial in cisplatin-ineligible, PD-L1–high, or platinum-ineligible patients.

The KEYNOTE-361 and DANUBE trials both turned out to be negative. Could you speak to the goals of these efforts and what was found? What did these trials teach us?

The KEYNOTE-361 trial was very similar to the IMvigor130 trial. Essentially [both trials] had 3 arms [that received] gemcitabine/platinum. This was in cisplatin-eligible or -ineligible patients, and it had gemcitabine/platinum plus pembrolizumab in this case. It also had a third arm of pembrolizumab alone. The primary comparison was gemcitabine/platinum versus gemcitabine/platinum plus pembrolizumab. This trial did not meet the primary end point. That's disappointing and [showcases the] hierarchical statistical comparison testing that could have been done. It basically led to an inability to compare pembrolizumab alone versus gemcitabine/platinum-based therapy.

The backdrop is the IMvigor130 trial in which it did exactly the same [in its] 3 arms, except you replace pembrolizumab with atezolizumab. In this one, there was an improvement in PFS by adding atezolizumab to gemcitabine/platinum, although the improvement was not overwhelming. It was a median improvement of PFS by around 2 months, and while the hazard ratio was not very inspiring, it was statistically significant at around 0.79. We still have to wait for survival in this trial, which is still pending. The combination of gemcitabine/platinum plus a PD-1 inhibitor is not going to change the standard of care at this time, unfortunately.

The other trial that came out was the DANUBE trial, which is sponsored by AstraZeneca. In this trial, again, in the first-line setting, cisplatin-eligible or -ineligible [patients were enrolled. The study compared the first-line combination of durvalumab plus tremelimumab with gemcitabine/platinum in all-comers. That comparison was negative and secondarily, it also compared durvalumab alone versus gemcitabine/platinum in PD-L1–high patients only. That was a co-primary primary endpoint and that comparison was also negative. This was all metastatic disease.

What are some data that have been read out with VEGF with or without PD-1/CTLA-4 inhibition in metastatic urothelial carcinoma?

Cabozantinib (Cabometyx) has been combined with nivolumab alone or plus ipilimumab; suffice to say that the combination looks promising. There are some promising immune modulation functions of cabozantinib, which is a VEGF inhibitor, as well as a MET inhibitor and TKI. This combination is undergoing further evaluation in a phase 2 trial.

As I said before, lenvatinib is undergoing evaluation in combination with pembrolizumab as a first-line therapy [option for] cisplatin-ineligible, PD-L1–high or platinum-ineligible patients. There is yet another VEGF inhibitor called sitravatinib (MGCD516); not only does it inhibit VEGF receptors, but it also inhibits TAM, TYRO3, AXL, and MER. This leads to an immune microenvironment that has activated T cells. This combination of nivolumab plus sitravatinib looks interesting in patients who progress post-checkpoint inhibition with a PD-1/PD-L1 inhibitor. When these patients received sitravatinib in combination with nivolumab, [they experienced] a response rate seen in approximately 20% to 25% of patients post-checkpoint inhibition, so that also appears to be a promising combination. The combination of VEGF plus PD-1/PD-L1 inhibitor looks promising in urothelial cancer. Hopefully, we'll see some improved outcomes in larger trials.

What are some other key take-home points regarding maintenance immunotherapy?

One thing to remember is that first-line pembrolizumab or atezolizumab, although quite reasonable in PD-L1–high patients, still do not have a phase 3 trial supporting that approach in terms of improved survival. There is still no phase 3 trial showing that first-line pembrolizumab is better than first-line gemcitabine/platinum followed by avelumab as a switch maintenance approach, whereas the switch maintenance approach now has a positive phase 3 trial with the JAVELIN Bladder 100 trial.

I also wanted to highlight that we should always support clinical trials in every setting. Remember that metastatic disease is still not curable in most cases. That is something to always offer patients, both in the first-line and in the salvage disease settings whenever possible.

Reference

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; abstr LBA1). doi:10.1200/JCO.2020.38.18_suppl.LBA1