The CheckMate 274 trial may have captured attention during the 2021 Genitourinary Cancers Symposium, but immunotherapy is not the only promising approach under study in urothelial carcinoma.
The CheckMate 274 trial may have captured attention during the 2021 Genitourinary Cancers Symposium, but immunotherapy is not the only promising approach under study in urothelial carcinoma, according to Guru P. Sonpavde, MD, who cited an abundance of research regarding antibody-drug conjugates and novel agents as reason for excitement.
“The major highlight of the 2021 Genitourinary Cancers Symposium was the phase 3 CheckMate 274 trial, which examined adjuvant nivolumab [Opdivo] vs placebo in [patients with] high-risk, muscle invasive urothelial carcinoma, but the 2021 Genitourinary Cancers Symposium was a very exciting meeting with a lot of advances for our patients,” said Sonpavde.
In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies, Sonpavde, director, Bladder Cancer, and physician, Dana-Farber Cancer Institute, discussed promising research in urothelial carcinoma.
Sonpavde: Patients in the CheckMate 274 trial were high risk because they had neoadjuvant cisplatin-based chemotherapy and had muscle invasive disease or higher-stage [disease] at radical cystectomy or nephroureterectomy. The study allowed [patients with] bladder cancer and upper track high-risk urothelial carcinoma. This study was a fairly large study [that enrolled] 709 patients, and the co-primary end points were disease-free survival [DFS] in the overall population, as well as in the PD-L1–high tumor population.
The study met its co-primary end points. The median DFS in the overall population was prolonged significantly, from a median of 10.9 months in the placebo arm to 21.0 months in the nivolumab arm; the hazard ratio was 0.70, the P value was highly significant at .0006, and when we looked at the PD-L1–high population, the primary end point of DFS was met. [In the PD-L1–high population], the median DFS was not reached in the nivolumab group and was 10.8 months in the placebo group. The hazard ratio was more robust in the PD-L1–high population at 0.53, and the P value was highly significant at .0004. The survival data have not been presented.
The investigators argued that this study is practice changing. We have to remember that the backdrop is the IMvigor010 trial, which looked at adjuvant atezolizumab [Tecentriq] and did not show an improvement in DFS. Interestingly, in a retrospective analysis of the IMvigor010 trial, patients who had postoperative circulating tumor DNA, [indicative of] minimal residual disease, derived a benefit from adjuvant atezolizumab.
Another study is ongoing called the AMBASSADOR trial [NCT03244384] that’s comparing adjuvant pembrolizumab [Keytruda] with observation, so there is no placebo control. The co-primary end points are overall survival [OS] and DFS in the overall population, and the benefit in the PD-L1–high population is a secondary end point. This study [could be] practice changing at least for the PD-L1–high group as we await survival data in the overall and the PD-L1–high group. The DFS benefit in an adjuvant checkpoint inhibitor setting is more likely to translate to improved survival than in the perioperative chemotherapy context.
The second study I wanted to highlight was the EV-301 trial, which is the confirmatory phase 3 study that examined enfortumab vedotin-ejfv [Padcev], an antibody-drug conjugate targeting Nectin-4 in the post-platinum and post–PD-1/PD-L1 setting of metastatic urothelial carcinoma. Enfortumab vedotin is already FDA approved in this setting based on a nonrandomized phase 2 trial. The [EV-301] trial should lead to full approval [of the agent]. In this trial, enfortumab vedotin improved OS significantly. The median survival improved from 9 months to 12.9 months; the hazard ratio was 0.70, and the progression-free survival was extended from 3.7 months to 5.6 months, with a hazard ratio of 0.61. The overall response rate [ORR] also improved from 17.9% with chemotherapy to 40.6% with enfortumab vedotin.
The third study I wanted to highlight was the EV-201 trial, which was a nonrandomized phase 2 trial of 91 patients. One of the cohorts [comprised patients in the third-line setting who had received prior] platinum and PD-1 inhibition. [This study] led to the [accelerated] approval of enfortumab vedotin in the third-line setting. The cohort presented at the 2021 Genitourinary Cancers Symposium was focused on the second-line cohort of patients who had received prior PD-1/PD-L1 inhibition. These patients were also cisplatin ineligible and had not received prior platinum-based chemotherapy.
The response rate was consistent with what has been seen with enfortumab vedotin in the third-line setting. The ORR was 52%, and very impressively, the complete response [CR] rate was 20%. The median duration of response was 10.9 months, and the median OS was 14.7 months. The toxicities were consistent with what has been seen before, which is peripheral neuropathy, rash, and hyperglycemia, [which comprised] the most common [toxicities]. The community standard in the second-line, post–PD-1 inhibitor setting is gemcitabine/carboplatin in cisplatin-ineligible patients. Perhaps enfortumab vedotin provides a strong option in this setting. Enfortumab vedotin [does not have a full] FDA approval in the second-line post–PD-1 inhibitor setting, so we await any guidelines in that direction.
The RETAIN BLADDER study was done in the perioperative setting. The standard of care in patients with muscle invasive bladder cancer has been neoadjuvant cisplatin-based combination chemotherapy, followed by radical cystectomy, regardless of the quality of response, because there is always some discord between clinical response and pathologic response. The RETAIN BLADDER trial looked at whether we could use tumor genomic information and clinical response to stratify patients, or at least offer patients a bladder-preserving approach of active surveillance.
If patients had a DNA damage repair mutation in the tumor that we know associates with pathologic CR in retrospective studies, and if patients also had a clinical CR to post-neoadjuvant chemotherapy, had no disease on cystoscopy and radiologic information, then these patients were offered active surveillance. This was a small study size of 71 patients. Patients who were on the active surveillance group had fairly impressive outcomes. The recurrence rate was 65% in this group.
However, about half of the recurrences were nonmuscle invasive; the other half were invasive, and a couple of patients had metastatic disease, which was fatal. There needs to be further study of this approach, but it’s a very exciting and promising approach. In fact, the Fox Chase Cancer Center group is looking at the combination of dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin] with a checkpoint inhibitor in the neoadjuvant setting to see if using genomic information and this chemoimmunotherapy approach could lead to even better outcomes.
The last study I want to highlight was also a nonrandomized study in nonmuscle invasive bladder cancer, an even earlier stage [of disease] than muscle invasive, in
Bacille Calmette-Guérin–unresponsive patients with carcinoma in situ [CIS]. In this trial, patients received a repetition of BCG in combination with a drug called N-803, which was also given intravesically, and this is an IL-15 super agonist. This was not a large study; only 71 patients were evaluable. At this time, the CR rate was an impressive 72%, which exceeded the lower boundary of the 95% confidence interval of 20%. At 1 year, 56% of patients maintained their CR, which is also impressive.
In patients with BCG-unresponsive disease with CIS, intravenous pembrolizumab is FDA approved. Therefore, this agent, N-803, looks promising in combination with BCG. Another drug that looks interesting is the Pseudomonas exotoxin conjugated with the EpCAM antibody, which is also given intravesically. We await the regulatory guidance on this agent as well as others in this setting. Also, instiladrin, which delivers the recombinant interferon alpha to the gene through an adenoviral vector has also shown promising activity in the field. All of these agents look promising in BCG-unresponsive, nonmuscle invasive bladder cancer CIS.
The combination of cabozantinib [Cabometyx] and nivolumab [Opdivo] with or without ipilimumab [Yervoy] was [also evaluated in] multiple cohorts of patients, including kidney cancer and urothelial cancer, and other rare variants. The 33 patients with metastatic urothelial carcinoma in this study were post-platinum patients who received this VEGF/PD-1 inhibitor approach.
In the urothelial carcinoma cohort, the ORR was 42%, which is impressive, with a CR rate of 21%. This is a promising strategy. Other VEGF/PD-1 combinations look promising in this setting in metastatic urothelial carcinoma, and these combinations have mostly been looked at in the post-platinum setting. One is sitravatinib plus nivolumab. We also have cabozantinib plus atezolizumab that has been looked at before, and also lenvatinib [Lenvima] plus pembrolizumab. Lenvatinib plus pembrolizumab is being examined in a first-line trial in cisplatin-ineligible patients that have PD-L1–high tumors or platinum-ineligible tumors vs pembrolizumab alone. We await the data from all of these exciting studies and their full publications.
We are waiting eagerly for more mature data from CheckMate 274. We want to look for a hint of survival in that trial. In all fairness, the study met its core primary end point, so I remain quite optimistic that [the results are] practice changing at a minimum for the PD-L1–high population. I am quite bullish given the all-comers population in this study.
[In terms of] exciting frontline studies, [we have] enfortumab vedotin plus pembrolizumab and also the CheckMate 901 study [NCT03036098] that’s comparing ipilimumab and nivolumab vs gemcitabine and platinum with co-primary end points in the cisplatin-ineligible group, as well as in the PD-L1–high group. In that study, there is also a sub-study comparing gemcitabine/cisplatin with gemcitabine/cisplatin and nivolumab in cisplatin-eligible patients only.
[We also have data from] the IMvigor130 study and the KEYNOTE 361 study, which evaluated platinum chemotherapy with or without checkpoint inhibitor combinations. Unfortunately, KEYNOTE 361 was negative, and the IMvigor130 study only showed a modest PFS benefit, but we don’t know about survival. In both of those studies, there was a signal for better benefit with the cisplatin backbone.
This sub-study in the CheckMate 901 study could be interesting, so I would look out for CheckMate 901, and of course the EV-302 study, which is looking at the combination of enfortumab vedotin plus pembrolizumab in the first-line setting.