Enfortumab vedotin-pembrolizumab beats chemo as 1L Tx for bladder cancer

In the phase III EV-302/KEYNOTE-A39 trial, the combination of enfortumab vedotin and pembrolizumab (EV+P) had a significant survival advantage over chemotherapy in the first-line treatment of patients with locally advanced metastatic urothelial carcinoma (la/mUC).

“We have not seen a survival signal before in UC. We have never beaten chemotherapy in the 1L setting. This is the first time we have achieved this goal,” said Dr Thomas Powles from the Queen Mary University of London, UK, during a Presidential Symposium at ESMO 2023.

“This is monumental in this field,” commented discussant Dr Andrea Apolo from the National Institutes of Health, Bethesda, Maryland, US.

EV+P cut mortality risk by 53 percent vs chemo (hazard ratio [HR], 0.47; p<0.00001), and median overall survival (OS) was nearly doubled (31.5 vs 16.1 months). Median survival follow-up was 17.2 months. [ESMO 2023, abstract LBA6]

There was a broad benefit with EV+P irrespective of patient subgroups, including cisplatin eligibility. HRs for the cisplatin-eligible and ineligible groups were 0.53 and 0.43, respectively, while median OS was 31.5 months and not reached (NR). The corresponding median OS in the chemo arm was 18.4 and 12.7 months.

“The median OS of 18.4 months is competitive compared with some of the historical trials … so this is the well-performing control arm [between the two] groups. The curves went and stayed apart in both groups,” said Powles.

EV+P also conferred benefit over chemo regardless of PD-L1 status. The respective HRs for the PD-L1 high and low groups were 0.49 and 0.44. Median OS remained longer with EV+P vs chemo (31.5 vs 16.6 months [high] and NR vs 15.5 months [low]).

PFS, ORR: EV+P still outdid chemo

EV+P also cut the risk of progression or death (HR, 0.45; p<0.00001) and doubled the median progression-free survival vs chemo (12.5 vs 6.3 months). Subgroup analyses also favoured EV+P across broad subgroups of patients regardless of platinum eligibility, PD-L1 expression, or visceral metastases, with HRs ranging between 0.36 and 0.53.

Objective response rate (ORR) was markedly higher with EV+P vs chemo (67.7 percent vs 44.4 percent; p<0.00001). Complete response rate with EV+P was 29.1 percent which, according to Powles, was “not something we have seen before.”

Median duration of response (DoR) was NR with EV+P and 7 months with chemo. “The durability, as well as the high response rate, translated into the OS signal,” explained Powles.

Poor long-term survival

Platinum-based chemo has been the standard of care (SoC) for bladder cancer, and while it was associated with responses, remissions were not durable, Powles noted.

“One of the issues around cisplatin or carboplatin has been renal dysfunction … Immune checkpoint inhibition as monotherapy turned out to not be transformative as it was unable to beat 1L chemo and is now established as maintenance therapy. But there remains a high unmet need,” he said.

“Median survival has been stuck at about 12–14 months for a generation. Long-term survival is really poor,” he continued. Two phase III trials evaluated a combination of chemo and atezolizumab or pembrolizumab; neither were able to achieve an OS advantage. [Lancet Oncol 2021;22:931-945; Lancet 2020;395:1547-1557]

EV, an antibody-drug conjugate targeting Nectin-4, has a survival advantage in platinum-refractory bladder cancer, as does pembrolizumab. [N Engl J Med 2021;384;1125-1135; J Clin Oncol 2019;37:2592-2600] “When you combine these two drugs in the 1L setting, you see a big bounce in response rate. The 68-percent seen [in the current study is] much higher than chemo, resulting in the accelerated FDA approval in cisplatin-ineligible patients,” said Powles.

The team randomized 886 participants (median age 69 years, 77 percent male) 1:1 to either IV EV 1.25 mg/kg on days 1 and 8 and IV pembrolizumab 200 mg on day 1 or chemo (cisplatin or carboplatin plus gemcitabine; six cycles max). More than half of the overall cohort were cisplatin eligible, 72 percent had visceral metastases (primarily lung), and ~60 percent had high PD-L1 expression. A third of EV+P recipients remained on treatment at the time of analysis.

Thirty-one percent of chemo recipients received maintenance avelumab. “The uptake of maintenance avelumab in the global community is somewhere between 30 and 50 percent, so we believe this is a representative control arm,” said Powles.

The overall incidence of treatment-related adverse events was higher with chemo than EV+P (70 percent vs 56 percent). Haematological toxicities were more prominent with chemo whereas with EV+P, the most common were peripheral neuropathy, rash, and hyperglycaemia.

First time to beat chemo

In sum, there was a significant reduction in the risk of death and progression, the benefit was seen across broad spectrums of prespecified subgroups irrespective of platinum eligibility, PD-L1 status, and visceral metastases, and the safety profile was manageable and aligned with that seen in phase I/II trials.

Moreover, compared with what was seen with platinum-based chemo or other combinations, EV+P had the highest ORR and a longer DoR, added Apolo. “There were also quick responses with EV+P. Time to response was ~2 months or the first restaging scan, which is really important for patients.”

“This is the first time we have managed to beat chemo in the 1L setting for OS despite multiple previous attempts … These results support EV+P as a potential new SoC for 1L la/mUC,” said Powles.

“These data are particularly impressive, and this combination will clearly become the new SoC for this cohort of patients,” said Apolo in a separate report. [dailyreporter.esmo.org/esmo-congress-2023/genitourinary-cancers/combination-therapies-with-immunotherapy-and-adcs-prolong-overall-survival-in-urothelial-carcinoma, accessed October 27, 2023]

“The results … have been long awaited as for over 2 decades, platinum-based chemo has been the SoC. It is very exciting that we have now identified a treatment combination that is superior to chemo in terms of OS,” she continued.

Best 1L regimen

“The future looks bright for patients with UC. EV+P has raised the bar for OS in mUC … It takes first place as the best 1L regimen in UC,” commented Apolo. “It is fantastic news that we can now improve survival for our patients. Multiple trials are ongoing … and we are eagerly awaiting their results.”