Research Runs Rampant With Immunotherapy in Urothelial Carcinoma

Sequential chemotherapy and immunotherapy became the preferred standard of care in patients with advanced urothelial carcinoma, based on findings from the phase 3 JAVELIN Bladder 100 trial, explained Petros Grivas, MD, PhD.

However, he added that the jury is still out on the potential merits of frontline immunotherapy following negative results from the phase 3 IMvigor130, KEYNOTE-361, and DANUBE trials.

“The JAVELIN Bladder 100 trial was a randomized phase 3 study comparing avelumab [Bavencio] plus best supportive care [BSC] with BSC alone in patients who had a response or stable disease [SD] to induction platinum-based chemotherapy. The results showed an overall survival [OS] benefit with switch maintenance avelumab, which has changed the standard of care in this population,” said Grivas.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies, Grivas, physician of the Seattle Cancer Care Alliance, associate professor in the Department of Medicine in the Division of Oncology and clinical director of the Genitourinary Cancers Program at the University of Washington School of Medicine, and associate member of the Clinical Research Division at Fred Hutchinson Cancer Center, discussed practice-changing, hypothesis-generating, and foundational research with checkpoint inhibitors and antibody-drug conjugates in urothelial cancer.

OncLive®: Have the primary and updated analyses from the JAVELIN Bladder 100 trial cemented the role of avelumab as maintenance therapy in patients who experience a response or have stable disease with frontline platinum-based chemotherapy?

Grivas: The hazard ratio for survival in all-comers was 0.69 and was even lower in those with PD-L1–positive tumors, which was a co-primary end point. Moreover, there was a significant progression-free survival [PFS] benefit in the intention-to-treat population [ITT], regardless of PD-L1 expression, but also in the subset of patients with PD-L1–positive tumors.

In terms of toxicity, we did not see anything different than what we know [of checkpoint inhibitors]. Avelumab was associated with a 7% [rate of] grade 3 immune-related adverse effects [AEs]. Overall, there was a 12% [rate of] any-grade treatment-emergent AEs that led to treatment discontinuation. Overall, avelumab was a very well-tolerated treatment. [The results] corroborated the data we have so far with checkpoint inhibitors in advanced disease. This trial cemented the role of avelumab switch maintenance [in this setting].

Updated data were presented at the 2021 Genitourinary Cancers Symposium, which showed that the PFS and OS benefit was [seen] regardless of the number of cycles [of chemotherapy] that patients received in the first-line setting. Whether I give 4, 5, or 6 cycles [of chemotherapy] in the first-line setting depends on the patient and how well they can tolerate treatment. Tolerance and AE profile, as well as response [factor into treatment decisions]. If I, for example, have a patient with a great response and good tolerance [to chemotherapy], I may try to push for 6 cycles. If someone has significant toxicity and stable disease, I may stop at 4 cycles. However, the presentation showed that the OS benefit with avelumab appears to be [evident] regardless of the number of cycles of chemotherapy that preceded [enrollment in] the clinical trial.

What do we know about the activity of avelumab in patient subgroups, potential biomarkers of response, and quality of life (QoL) on the PD-L1 inhibitor?

I had the opportunity to [present some updated data] at the [2020] ESMO Virtual Congress a few months ago on patient subgroups—for example, patients with complete or partial response or SD to prior induction chemotherapy. The benefit with avelumab maintenance appears to be consistent across the board with variable degrees of benefit.

We also saw some very interesting biomarker data at ESMO. Not practice impacting, but hypothesis-generating biomarker data, looking at tumor tissue biomarkers, Fcγ receptor polymorphism, DNA repair gene mutations, PD-L1, TMB, molecular subtyping, signatures, etc.

We also showed some patient-reported outcome and QOL data, suggesting that avelumab did not negatively impact QOL in those patients. These are all important data, and we plan to update our data at future meetings, so stay tuned for more data.

Have any analyses been done to determine whether avelumab is being used as the predominant standard of care following induction chemotherapy in these patients?

At this point, the standard of care in most patients appears to be platinum-based chemotherapy followed by switch maintenance avelumab. The approval that came in 2020 has been adopted in clinical practice.

We presented a poster at the 2021 Genitourinary Cancers Symposium, and we talked to oncologists, physicians, and nurses who have experience in oncology, and we asked which paradigm they use: if they started with chemotherapy, do they [prescribe] maintenance avelumab or concurrent chemoimmunotherapy? The vast majority answered chemotherapy followed by maintenance avelumab, suggesting that the standard of care is being picked up.

I also want to make the point that we still are waiting for longer-follow up from IMvigor130 to see whether the chemoimmunotherapy combination will reach statistical significance. We have not seen updated data since the presentation at the 2019 ESMO Congress. Overall, the biomarker data are interesting, and I am looking forward to more advances in this disease.

Could the exploratory analysis that was presented from the atezolizumab (Tecentriq) monotherapy arm of the IMvigor130 trial affect frontline treatment recommendations in cisplatin-ineligible patients?

IMvigor130 tried to answer 2 questions. One was [regarding the value of] concurrent combination therapy with chemotherapy plus atezolizumab vs chemotherapy plus placebo––arm A vs arm C. In the hierarchical statistical analysis plan, there was also a question about [the value of] atezolizumab vs chemotherapy––arm B vs arm C. This data set was updated at the 2021 Genitourinary Cancers Symposium, and patients who had high PD-L1 expression, specifically cisplatin-ineligible patients, experienced a significant improvement in OS with atezolizumab vs chemotherapy.

This was exploratory and hypothesis generating. There were very few numbers; about 50 and 43 patients [were included] in the 2 groups, [respectively], so it was a very small sample size. I do not think [these data are] practice changing.

However, [they] can inform those discussions in patients who refuse chemotherapy. Patients who have high PD-L1 high expression, have lymph node–only disease, and are not fit for cisplatin are reasonable to think about for checkpoint inhibition. However, the majority of patients in our practice, if they’re not fit for cisplatin, get carboplatin/gemcitabine followed by avelumab maintenance.

We don’t have a comparison between atezolizumab alone and chemotherapy followed by avelumab maintenance. That’s a caveat. However, all of these data can inform your discussions, and people can make decisions based on the totality of available data.

Were any new safety signals identified in the updated analysis of the IMvigor130 trial?

We did not see any concern about safety or new safety signals. Atezolizumab alone, like avelumab alone, has known risks of immune-related AEs [irAEs], but the overall incidence of severe irAEs is low. The combination of chemotherapy plus atezolizumab definitely has a chance of added toxicity and cost, which is another thing to keep in mind, especially in the absence of OS benefit, at least at the last follow-up. However, the combination appears to be safe and effective. [Toxicity] seems manageable, which is something we knew from other studies as well.

The totality of the data now support chemotherapy followed by switch maintenance avelumab in patients with disease control, and in those who cannot tolerate any chemotherapy, a checkpoint inhibitor alone is a perfect, approved option in the frontline setting. In the United States, the FDA allows the use of a checkpoint inhibitor alone, regardless of PD-L1 expression in patients who cannot get any chemotherapy, except for carboplatin.

In addition to the IMvigor130 trial, the KEYNOTE-361 and DANUBE trials did not show a benefit with frontline immunotherapy. Is frontline immunotherapy still a strategy worth exploring based on these results?

The KEYNOTE-361 trial compared chemotherapy and pembrolizumab [Keytruda] with chemotherapy alone and did not show PFS or OS benefit with the addition of pembrolizumab, which was a surprise and also kind of confirmed the lack of OS benefit with chemoimmunotherapy in the frontline setting, as in the IMvigor130 trial. Both trials failed to show a significant prolongation in OS when we combined chemoimmunotherapy in the frontline setting.

The other important trial was the DANUBE trial, which was presented at the 2020 ESMO Virtual Congress and compared durvalumab [Imfinzi] and tremelimumab, an anti–PD-L1/CTLA-4 combination, vs chemotherapy in all-comers. In the ITT population, there was a trend but no significant OS benefit with an immunotherapy doublet compared with chemotherapy.

Even if you look at PD-L1–high patients, now we have durvalumab and pembrolizumab, and in both those trials, there was no significant OS benefit with durvalumab or pembrolizumab vs chemotherapy alone. We saw the signal in the atezolizumab trial, but based on statistical design, this was a subset that was not significant. We still [have to determine which] patients respond better to chemotherapy and respond to immunotherapy, and maybe there’s significant overlap at the molecular level, which might explain why we do not see a lot of additive effect if you put [these agents] together. Perhaps that is why the sequential strategy based on the JAVELIN 100 trial works—because you sequence them over time.

Which studies presented at the 2021 Genitourinary Cancers Symposium have the most practice-changing potential?

We saw some very interesting genomics data in nonmuscle invasive and muscle invasive disease. We also saw a couple of interesting neoadjuvant trials looking at chemoimmunotherapy that were hypothesis generating and definitely support the ongoing phase 3 trials with chemoimmunotherapy in cisplatin-eligible patients in the neoadjuvant and adjuvant settings.

We also saw some very exciting data with adjuvant nivolumab [Opdivo] in the CheckMate 274 trial. These data were really impressive with disease-free survival [DFS] benefit in all-comers, but a higher degree of DFS benefit in the PD-L1–high subgroup. It remains to be seen whether these data will result in an OS benefit or whether the FDA and European Medicines Agency will approve the agent based on DFS benefit. Some people want to see an OS benefit.

There is also significant interest with antibody-drug conjugates [ADCs]. We saw very impressive data with [enfortumab vedotin-ejfv (Padcev)] from cohort 2 of the EV-201 trial. The phase 3 EV-301 trial showed OS benefit with enfortumab vedotin vs single-agent chemotherapy in the third-line setting also, cementing the role of enfortumab vedotin, with level 1 evidence, in patients with progression on prior platinum chemotherapy and checkpoint inhibition.

Sacituzumab govitecan-hziy [Trodelvy] is another ADC that’s being tested, and I had the honor to present a trial in progress with single-agent sacituzumab govitecan compared with single-agent taxane or eribulin (Halaven) in a phase 3 trial design. It’s a very similar design to the EV-301 trial, looking at OS as a primary end point. We’re hopeful that we can accrue to the TROPiCS-04 trial to evaluate whether the TROPHY-U-01 cohort 1 data hold true. TROPHY-U-01 was a phase 2 single-arm study with sacituzumab govitecan, where we showed an overall response rate of 27% at the 2020 ESMO Virtual Congress. This definitely sets the stage for the phase 3 TROPiCS-04 trial. We’re very excited about all these data and are looking forward to more advances in the field, and hopefully more options for our patients.

Is there anything else that you wanted to highlight?

There are some interesting data with anti-HER2 ADCs. There are a lot of data about molecular profiling, and somatic but also germline mutations. That’s an important opportunity to highlight the need to get a good family history for the broader family of the patient. I have a low threshold in my practice of referring patients with urothelial cancer to genetic counselors, because germline mutations could be relevant to the patient, but also to the broader family for prevention and screening.

In addition to that, there’s also some discussion about the role of circulating tumor DNA [ctDNA] as a separate biomarker in this disease. There are some interesting data from the IMvigor010 adjuvant trial, suggesting that ctDNA could be used in those patients to identify a subset of patients with high risk for recurrence. [Data from IMvigor010] could support the phase 3 adjuvant IMvigor011 trial.

[Ultimately,] enrolling in clinical trials is very important because they are a vehicle of success. That’s how we can move the field forward. We’re looking forward to follow-up data from the IMvigor130 trial. It’s interesting hypothesis generating data with the biomarker work from all these trials. If we think about level 1 evidence, if you start with platinum-based chemotherapy, either gemcitabine/cisplatin or gemcitabine/carboplatin, in patients who experience response or stable disease, we should follow the standard of care, which is avelumab maintenance if the patient can tolerate immunotherapy. It’s a great thing to see that the median OS of those patients now exceeds 2 years. [We’re] definitely moving the field forward.