CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: December 22, 2023
Expiration: December 21, 2024
EV-302/KEYNOTE-A39: Enfortumab Vedotin Plus Pembrolizumab vs Chemotherapy for Treatment-Naive Advanced Urothelial Cancer
Daniel P. Petrylak, MD:
The combination of the Nectin-4-directed antibody‒drug conjugate (ADC) enfortumab vedotin and the immune checkpoint inhibitor (ICI) pembrolizumab is approved for use in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) based on evidence from the EV-302 trial.[Enfortumab vedotin PI] Previously, accelerated approval was granted for patients who are not eligible for cisplatin-containing chemotherapy based on a demonstrated confirmed objective response rate of 64.5% with the combination in this population.[O’Donnell 2023] The randomized phase III EV-302 study was undertaken to compare enfortumab vedotin plus pembrolizumab vs chemotherapy in patients with previously untreated la/mUC regardless of cisplatin eligibility or PD-L1 expression status.[Powles 2023]
Patients could not have received neoadjuvant or adjuvant chemotherapy within 1 year of study entry. They had to be eligible for platinum (cisplatin or carboplatin). Patients were randomly assigned to receive enfortumab vedotin (1.25 mg/kg on Days 1 and 8) plus pembrolizumab (200 mg on Day 1) every 3 weeks with a maximum of 35 cycles of pembrolizumab, or gemcitabine (Days 1 and 8) plus cisplatin or carboplatin (Day 1) every 3 weeks for up to 6 cycles. The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints were overall response rate (ORR), duration of response (DoR), disease control rate, and PFS by investigator review. Quality of life (QoL) and pain symptoms also were measured.
EV-302/KEYNOTE-A39: Baseline Characteristics
Daniel P. Petrylak, MD:
Approximately three quarters of enrolled patients were male, and the median age was 69 years. Approximately two thirds of patients were White, and nearly one quarter were from North America.[Powles 2023] Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. As one would expect, the lower urinary tract was the predominant primary site. Visceral metastases were detected in 72% of patients, and liver metastases were detected in 22%. PD-L1 expression was high (combined positive score ≥10) in 58% of patients.
EV-302/KEYNOTE-A39: PFS per BICR (Coprimary Endpoint)
Daniel P. Petrylak, MD:
The median PFS per BICR was 12.5 months with enfortumab vedotin plus pembrolizumab and 6.3 months with chemotherapy (HR: 0.45; 95% CI: 0.38-0.54; P <.00001).[Powles 2023] The data are consistent with what we have seen for chemotherapy in the past and are similar to what we saw in the EV-103 study for enfortumab vedotin plus pembrolizumab.[O’Donnell 2023]
EV-302/KEYNOTE-A39: Subgroup Analysis of PFS per BICR
Daniel P. Petrylak, MD:
The PFS benefit observed with enfortumab vedotin plus pembrolizumab vs chemotherapy was observed across subgroups including age, sex, ECOG PS, disease location, presence of liver metastases, PD-1 expression category, and cisplatin eligibility.[Powles 2023]
EV-302/KEYNOTE-A39: OS (Coprimary Endpoint)
Daniel P. Petrylak, MD:
The trial also met its other coprimary endpoint, demonstrating a more than doubling of OS with enfortumab vedotin plus pembrolizumab resulting in a median OS of 31.5 months vs 16.1 months with chemotherapy (HR: 0.47; 95% CI: 0.38-0.58; P <.00001).[Powles 2023] This is probably the longest OS outcome I have observed with any combination therapy in urothelial carcinoma (UC). It is longer than what we saw in the EV-103 trial, in which enfortumab vedotin plus pembrolizumab was associated with a median OS of 22.3 months.[O’Donnell 2023] The median OS in the chemotherapy arm was a bit shorter than one would expect; I would have expected it to be in the range of 23 months. A potential reason for the shorter survival in the chemotherapy arms is the predominance of visceral disease. Chemotherapy works well for nodal disease, but in visceral disease, it is not as effective.[Galsky 2013]
This may be where the OS benefit occurs—in improving effectiveness in patients who normally would have had a rapid progression and not responded to chemotherapy or immunotherapy.
EV-302/KEYNOTE-A39: Subgroup Analysis of OS
Daniel P. Petrylak, MD:
OS subgroup analyses again showed an improvement with enfortumab vedotin plus pembrolizumab vs chemotherapy for all groups examined.[Powles 2023] PD-L1 expression status did not affect the OS benefit.
EV-302/KEYNOTE-A39: Confirmed Overall Response per BICR
Daniel P. Petrylak, MD:
The confirmed ORR was significantly higher with enfortumab vedotin plus pembrolizumab vs chemotherapy at 67.7% vs 44.4%, respectively (P <.00001).[Powles 2023] The complete response (CR) rate of 29.1% with enfortumab vedotin plus pembrolizumab was pretty remarkable compared with the 12.5% observed with chemotherapy. The ORR observed with chemotherapy is consistent with what we have seen in the past. The median DoR was not reached with enfortumab vedotin plus pembrolizumab and was 7.0 months with chemotherapy.
EV-302/KEYNOTE-A39: Subsequent Therapies
Daniel P. Petrylak, MD:
Regarding subsequent therapies, in the enfortumab plus pembrolizumab arm, approximately one quarter of patients received platinum-based chemotherapy as their first subsequent systemic therapy.[Powles 2023] Only 1.6% of patients received an ICI, as one would expect, and 2.5% of patients received an unspecified therapy.
In the chemotherapy arm, approximately 4% of patients received further platinum-based chemotherapy, which makes sense given the initial treatments, and 59% received an ICI. Approximately 32% of patients received maintenance therapy, predominantly avelumab. This was a concern with this trial—that the trial was amended to allow for patients to receive maintenance therapy. ICIs were administered following progression on chemotherapy in 26% of patients.
It is unknown how many patients in the chemotherapy arm received enfortumab vedotin. We know from prior retrospective studies that the OS in this setting is approximately 10-14 months.[Zschäbitz 2023; Koshkin 2022] Use of subsequent enfortumab vedotin likely would have improved survival in the control arm and may have narrowed the gap between the median OS of 30 months reported with enfortumab vedotin plus pembrolizumab and 16 months reported with chemotherapy.
EV-302/KEYNOTE-A39: Safety
Daniel P. Petrylak, MD:
In terms of adverse events (AEs), nothing was really surprising.[Powles 2023] Peripheral sensory neuropathy occurred in 50% of patients receiving enfortumab vedotin plus pembrolizumab (3.6% grade ≥3). Note that this figure does not differentiate grade 1 from grade 2, and there is a clinical difference between the two.
Anemia (56.6%) and neutropenia (41.6%) were the most common AEs observed with chemotherapy. Treatment-related AEs leading to death in the enfortumab vedotin plus pembrolizumab arm were 1 patient each with asthenia, diarrhea, immune-mediated lung disease, and multiple organ dysfunction. In the chemotherapy arm, deaths due to treatment-related AEs were 1 patient each with febrile neutropenia, myocardial infarction, neutropenic sepsis, and sepsis.
EV-302/KEYNOTE-A39: Treatment-Related AEs of Special Interest With Enfortumab Vedotin
Daniel P. Petrylak, MD:
Treatment-related AEs of special interest with enfortumab vedotin included 63% any-grade peripheral neuropathy and 6.8% grade ≥3. Of grade ≥3 events, 4.3% were sensory, and 2.7% were motor. With chemotherapy, the rate of any-grade peripheral neuropathy was 12.2%, with no grade ≥3 events.[Powles 2023]
Ocular disorders were seen in approximately one quarter of patients receiving enfortumab vedotin and 18.6% were dry eye events, but none of the ocular disorders was grade ≥3. Hyperglycemia is a known complication of enfortumab vedotin, and grade ≥3 hyperglycemia was observed in 6.1% of patients.
EV-302/KEYNOTE-A39: Treatment-Emergent AEs of Special Interest With Pembrolizumab
Daniel P. Petrylak, MD:
Expected AEs with pembrolizumab included severe skin reactions (17.0%; 11.8% grade ≥3), which are sometimes difficult to distinguish from those associated with enfortumab vedotin; hypothyroidism (10.7%; 0.5% grade ≥3); pneumonitis (9.5%; 3.6% grade ≥3); hyperthyroidism (4.5%; 0.2% grade ≥3); hepatitis (3.2%; 1.8% grade ≥3); and colitis (2.7%; 1.6% grade ≥3).[Powles 2023] Rates of these inflammatory-type AEs were lower with chemotherapy, as would be expected, whereas more toxic reactions are more common with chemotherapy.
EV-302/KEYNOTE-A39: Clinical Implications
Daniel P. Petrylak, MD:
In summary, enfortumab vedotin plus pembrolizumab should be considered the standard of care for both cisplatin-eligible and cisplatin-ineligible patients. In my opinion, it will now supplant gemcitabine/cisplatin or gemcitabine/carboplatin as front-line therapy. The question will be what to do after enfortumab vedotin plus pembrolizumab upon disease progression. That is where gemcitabine/carboplatin and gemcitabine/cisplatin may play a role.
Regarding the sequencing of therapies, from this analysis enfortumab vedotin plus pembrolizumab should be the front-line therapy. We do not know how many patients in the control arm ultimately received enfortumab vedotin. I think this could have an influence on survival, but I do not think it will negate the difference that we see in the OS benefit.
An ongoing trial is evaluating enfortumab vedotin plus pembrolizumab in the neoadjuvant setting (EV-ECLIPSE, NCT05239624). If this approach is found to be beneficial, the optimal sequencing of therapies and the potential role of subsequent ICI therapy will be unknown. There are also questions regarding the potential efficacy of enfortumab vedotin plus pembrolizumab in patients who develop recurrence within 1 year of receiving adjuvant ICIs.
CheckMate 901: Nivolumab Plus Platinum-Based Chemotherapy vs Platinum-Based Chemotherapy for Treatment-Naive Advanced Urothelial Carcinoma
Daniel P. Petrylak, MD:
The randomized phase III CheckMate 901 trial evaluated gemcitabine/cisplatin with and without nivolumab in patients with previously untreated unresectable or metastatic UC who were eligible for cisplatin therapy.[van der Heijden 2023a; van der Heijden 2023b] The trial enrolled 608 patients who were randomly assigned to receive nivolumab plus gemcitabine/cisplatin or gemcitabine/cisplatin, administered for up to 6 cycles. Patients in the nivolumab arm could continue receiving nivolumab as monotherapy after completing the combination phase until progression or unacceptable toxicity. The primary endpoints were OS and PFS by BICR. Key secondary endpoints were OS and PFS by PD-L1 ≥1% and health-related QoL. Exploratory endpoints included objective response rate by BICR and safety.
CheckMate 901: Baseline Characteristics
Daniel P. Petrylak, MD:
The median age of enrolled patients was 65 years; approximately 77% were male, and approximately three quarters had urinary bladder cancer.[van der Heijden 2023a; van der Heijden 2023b] Overall, characteristics were similar to those in the EV-302 trial.[Powles 2023] There was a higher prevalence of treatment in non-US sites, with only 6% to 7% of patients enrolled from the United States. Approximately 36% of patients had a tumor PD-L1 expression ≥1%, and 21% had liver metastases in each arm, again similar to the EV-302 trial.
CheckMate 901: Overall Survival by BICR (Coprimary Endpoint)
Daniel P. Petrylak, MD:
There was a significant 2.8-month improvement in OS with nivolumab plus gemcitabine/cisplatin vs gemcitabine/cisplatin, with a median OS of 21.7 months vs 18.9 months, respectively (HR: 0.78; 95% CI: 0.63-0.96; P = .02).[van der Heijden 2023a; van der Heijden 2023b] The 24-month OS rates were 46.9% and 40.7%, respectively. The OS benefit with the addition of nivolumab was consistent across most subgroups.
CheckMate 901: Progression-Free Survival by BICR (Coprimary Endpoint)
Daniel P. Petrylak, MD:
There was a statistically significant improvement in PFS with nivolumab plus gemcitabine/cisplatin vs gemcitabine/cisplatin alone, with a median PFS of 7.9 months and 7.6 months, respectively (HR: 0.72; 95% CI: 0.59-0.88; P = .001).[van der Heijden 2023a; van der Heijden 2023b] Although median PFS outcomes were similar, PFS rates were higher with the addition of nivolumab to gemcitabine/cisplatin at 12 months (34.2% vs 21.8%) and at 24 months (23.5% vs 9.6%).
The PFS benefit was observed in most subgroups, including in patients with PD-L1 ≥1%. The PFS benefit was greater in patients with PD-L1 ≥1% vs PD-L1 <1%; this is in contrast to the EV-302 study.
CheckMate 901: Response
Daniel P. Petrylak, MD:
The objective response rate was 57.6% with nivolumab plus gemcitabine/cisplatin and 43.1% with gemcitabine/cisplatin.[van der Heijden 2023a; van der Heijden 2023b] CR rates were 21.7% and 11.8%, respectively. The median DoR was longer by approximately 2 months with the addition of nivolumab (9.5 months vs 7.3 months), and the median duration of CR was 37.1 months with nivolumab vs 13.2 months with chemotherapy alone, reflecting the benefit of an ICI. Median time to response was 2.1 months in both arms. Health-related QoL was similar between arms.
CheckMate 901: Safety
Daniel P. Petrylak, MD:
Treatment-related AEs were as expected with the combination of chemotherapy and immunotherapy.[van der Heijden 2023a; van der Heijden 2023b] Rates of grade ≥3 hematologic AEs were higher with nivolumab plus gemcitabine/cisplatin vs gemcitabine/cisplatin, including anemia (22% vs 18%), neutropenia (19% vs 15%), decreased platelet count (8% vs 5%), and decreased white blood cell count (10% vs 4%). Most other AEs occurred at similar frequencies between arms.
CheckMate 901: Clinical Implications
Daniel P. Petrylak, MD:
Although head-to-head data are lacking, I would expect that enfortumab vedotin plus pembrolizumab will be favored vs nivolumab plus gemcitabine/cisplatin given the large increases in OS and PFS observed in the EV-302 study.[Powles 2023] The question is, in which subgroup can we consider using the nivolumab plus chemotherapy regimen? I would like to see subgroup analyses of the patients with lymph node‒only disease for both studies, as it may not be necessary to use as aggressive a treatment in those patients.
Although a head-to-head trial would be the best way to answer these questions, that may not be feasible.
DAD Trial: Study Design
Daniel P. Petrylak, MD:
Given that the Nectin-4-targeting ADC enfortumab vedotin and the TROP-2‒targeting ADC sacituzumab govitecan differ in their targets and cytotoxic payloads, there may be a rationale for administering these 2 agents in combination. The phase I DAD trial was undertaken to evaluate the safety and maximum tolerated doses of enfortumab vedotin plus sacituzumab govitecan in patients with treatment-resistant metastatic UC.[McGregor 2023a; McGregor 2023b] This nonrandomized, dose-escalation trial evaluated sacituzumab govitecan administered at doses from 6-10 mg/kg in combination with enfortumab vedotin administered at 1.0-1.25 mg/kg, each given on Days 1 and 8 every 21 days. The trial enrolled patients with la/mUC with progression on prior platinum-based chemotherapy plus immunotherapy or on 1 line of therapy for cisplatin-ineligible patients. Patients could not have active central nervous system metastases, ongoing toxicities from prior treatment (grade ≥2), or uncontrolled diabetes.
The primary endpoint was cycle 1 dose-limiting toxicities (DLTs), which included neutropenic fevers, thrombocytopenic bleeding, grade 3 neuropathy, or non‒grade 3 hematologic toxicity lasting >1 week or requiring a 3-week treatment interruption. Secondary endpoints were objective response rate, PFS, and OS. Results were presented after a median follow-up of 15 months.
DAD Trial: Baseline Characteristics
Daniel P. Petrylak, MD:
The median age of the 23 enrolled patients was 70 years; 78% were male. Liver metastases were present in 26% of patients.[McGregor 2023a; McGregor 2023b] Histology was pure urothelial in 70% of patients. Approximately one half of patients (52%) had received 1-2 prior lines of therapy. The primary site of disease was the bladder (70% of patients).
DAD Trial: Maximum Tolerated Dose
Daniel P. Petrylak, MD:
DLTs were reported at each dose level and included febrile neutropenia, sepsis, delays in treatment, and mucositis.[McGregor 2023a; McGregor 2023b]
DAD Trial: Adverse Events
Daniel P. Petrylak, MD:
AEs were primarily additive with the 2 agents.[McGregor 2023a; McGregor 2023b] Diarrhea occurred in 52.2% of patients, as would be expected with sacituzumab govitecan. Grade 4 neutropenia occurred in 17.4% of patients, which is a higher incidence than has been observed with either drug separately. Grade 3 fatigue, nausea, and urinary tract infections occurred in 8.7%, 4.3%, and 13% of patients, respectively. Urinary tract infections also were reported in the phase III trial of enfortumab vedotin.[Enfortumab vedotin PI] These patients do have a prolonged urinary tract, which could increase the risk of these types of infections. One incidence of grade 5 pneumonitis potentially related to enfortumab vedotin occurred in 1 patient.
DAD Trial: Recommended Phase II Dose
Daniel P. Petrylak, MD:
Based on the statistical analysis of the dose escalation, the recommended phase II dose is sacituzumab govitecan at 8 mg/kg plus enfortumab vedotin at 1.25 mg/kg on Days 1 and 8 of a 21-day cycle.[McGregor 2023a; McGregor 2023b]
DAD Trial: Efficacy Outcomes
Daniel P. Petrylak, MD:
The objective response rate was 70%, ranging from 50% in dose level 3 to 78% in dose level 1.[McGregor 2023a; McGregor 2023b] Of 23 patients enrolled, 9 had ongoing responses at the 15-month median follow-up. The 12-month PFS and OS rates were 41% and 85%, respectively.
DAD Trial: Clinical Implications
Daniel P. Petrylak, MD:
Given the advance made with enfortumab vedotin plus pembrolizumab in the first-line setting, a key question is whether this combination of sacituzumab govitecan and enfortumab vedotin could be integrated with pembrolizumab and moved up front as a new first-line treatment.[McGregor 2023a; McGregor 2023b] Another interesting question could be whether this combination could be used in the neoadjuvant setting.
PSMAfore: 177Lu-PSMA-617 vs Changing Androgen Receptor Pathway Inhibitor in Previously Treated Metastatic Castration-Resistant Prostate Cancer
Daniel P. Petrylak, MD:
Finally, an important abstract in prostate cancer presented at ESMO 2023 was the phase III PSMAfore trial, which compared 177Lu-PSMA-617 vs a change in androgen receptor pathway inhibitor (ARPI) in patients with metastatic castration-resistant prostate cancer with progression on a second-generation ARPI (N = 547).[Sartor 2023]
The trial met its primary endpoint, demonstrating a significant improvement in radiographic PFS (rPFS) with 177Lu-PSMA-617 vs an ARPI change with a median rPFS of 12.02 months vs 5.59 months, respectively (HR: 0.43; 95% CI: 0.33-0.54), in this update. Median OS in the intention-to-treat population was 19.25 months vs 19.71 months, respectively, but 84.2% of patients who discontinued the control treatment because of progression had crossed over to receive 177Lu-PSMA-617. Secondary efficacy endpoints also favored 177Lu-PSMA-617.
Currently 177Lu-PSMA-617 is the only FDA approved therapy for those patients with prior taxane and next generation antiandrogen treatment. If regulatory approval is granted, healthcare professionals potentially could consider 177Lu-PSMA-617 for patients who decline, or are ineligible for, taxanes after a next-generation anti-androgen.
Back
