CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 18, 2022
Expiration: April 17, 2023
Daniel P. Petrylak, MD:
Cisplatin‑based chemotherapy is the standard of care for neoadjuvant treatment of MIBC, with a pCR rate of 36% to 42% and a median OS of 77 months.11-13 Patients ineligible for cisplatin receive chemoradiation therapy or radical cystectomy with no dissection but the possibility of adjuvant nivolumab afterward.
The cisplatin-ineligible population is the focus of our next study. At ASCO GU 2022, I presented this initial analysis of cohort H from the ongoing phase I/II EV-103 study evaluating neoadjuvant enfortumab vedotin followed by surgery.14 The 22 patients in this cohort had muscle-invasive disease and were cisplatin ineligible at enrollment. Enfortumab vedotin was given at a dose of 1.25 mg/kg on Day 1 and Day 8 of three 21-day cycles. This is what I call a “lite” version of enfortumab vedotin because it skips the standard dose on Day 15. Following the third cycle, patients underwent cystectomy plus pelvic lymph node dissection. After surgery, follow-up imaging was done every 12 weeks for the first 2 years and then every 24 weeks thereafter.
The primary endpoint for this cohort is the pCR rate. Secondary endpoints include downstaging rate, event‑free survival, disease‑free survival (DFS), OS, patient‑related outcomes, biomarkers, and safety.
Daniel P. Petrylak, MD:
The 22 patients are predominantly male (90.9%) and all of white race, of whom 95.5% are current or former smokers.14 The most common current disease stage was cT2N0 in 15 patients (68.2%), and 15 patients (68.2%) had transitional cell carcinoma (TCC) only by histology. TCC with squamous differentiation was present in 3 patients (13.6%), and the remaining 4 patients (18.2%) had TCC with other histologic variants.
All patients met ≥1 Galsky criteria for cisplatin ineligibility, with 11 patients (50.0%) having inadequate renal function. Surprisingly, 9 patients (40.9%) had grade ≥2 hearing loss, and 1 patient (4.5%) had both inadequate renal function and grade ≥2 hearing loss.
Daniel P. Petrylak, MD:
All 3 cycles of neoadjuvant therapy were completed by 19 of the 22 patients, and all patients underwent cystectomy without delays.14 One patient underwent a partial cystectomy, and the rest underwent radical cystectomy plus pelvic lymph node dissection.
Daniel P. Petrylak, MD:
Antitumor activity was observed with neoadjuvant enfortumab vedotin, with 8 patients (36.4%) achieving pCR (the primary endpoint) and 11 patients (50.0%) having pathologic downstaging by central pathology review.14
Daniel P. Petrylak, MD:
There were no new safety signals identified.14 Grade ≥3 TEAEs occurred in 4 patients (18%) and included asthenia, dehydration, erythema multiforme, hyperglycemia, postprocedural urine leak, rash, and intestinal obstruction. None of the 5 patients with hyperglycemia had preexisting diabetes, and none of the other AEs reached grade 4/5. There were 3 postoperative deaths: 1 from pulmonary embolus related to surgery, 1 from cardiac arrest related to surgery, and 1 from acute kidney injury.
TEAEs leading to dose reduction of enfortumab vedotin occurred in 2 patients (9.1%), with 1 patient experiencing grade 2 dysgeusia and the other experiencing grade 2 diarrhea. Enfortumab vedotin–related TEAEs led to treatment discontinuation in 3 patients (13.6%) due to grade 3 dehydration, grade 3 erythema multiforme, and grade 3 rash maculopapular.
Daniel P. Petrylak, MD:
Antitumor activity was observed with neoadjuvant enfortumab vedotin in patients with cisplatin-ineligible MIBC with a pCR rate of 36%.14 All patients underwent surgery without delay, and no new safety signals were identified. We concluded that the results support ongoing phase II/III trials assessing enfortumab vedotin in this disease setting. These trials include cohort L of the present EV-103 study (NCT03288545), which is evaluating neoadjuvant and adjuvant enfortumab vedotin in cisplatin-ineligible MIBC, and the phase III EV‑303/KEYNOTE-905 (NCT03924895) and EV‑304/KEYNOTE-B15 (NCT04700124) trials, which are evaluating perioperative enfortumab vedotin plus pembrolizumab in cisplatin-ineligible MIBC.
Dr. Choueiri, what are your thoughts about these results?
Toni K. Choueiri, MD:
I think we need a randomized study here to determine whether this is truly a viable option. Enfortumab vedotin is indeed active in this setting, but cisplatin-ineligible patients go directly to cystectomy, and I do not know if giving enfortumab vedotin beforehand is truly superior to current options. As Dr. Petrylak noted earlier, the pCR rate of 36% reported in this study is in line with the rate reported for cisplatin‑based combinations.12,13
Daniel P. Petrylak, MD:
I agree. We need to see what the final randomized data show. The data in metastatic disease are positive, suggesting that there may be a neoadjuvant benefit with enfortumab vedotin.15,16
Toni K. Choueiri, MD:
We have all been waiting for initial data from the BAYOU trial. This is an international double-blind phase II study of first‑line durvalumab with or without olaparib in 154 patients with unresectable metastatic urothelial cancer.17 Participants were not preselected for biomarkers, although there was stratification by HRR status (HRRm vs HRR wild type) and Bajorin risk index (0 vs 1 vs 2). Patients were randomized to receive durvalumab plus olaparib vs durvalumab plus placebo. At the time of the data cutoff, the median follow-up was 9.8 months in the arm containing olaparib and 10.7 months in the placebo arm.
The primary endpoint is investigator‑assessed PFS and secondary endpoints include PFS in HRRm, OS, and ORR. Safety and tolerability are other endpoints. Rosenberg and colleagues presented results from BAYOU at ASCO GU 2022.17
Toni K. Choueiri, MD:
This was a small study with fewer than 80 patients in each arm.17 Baseline characteristics were balanced between arms. Approximately two thirds of the patients had visceral metastases, and approximately 30% had 2 Bajorin risk factors. Approximately 20% of patients were HRRm.
Toni K. Choueiri, MD:
As I mentioned earlier, participants were not preselected based on HRR status, but HRR status was a stratification factor during randomization.17 HRR status was determined by testing tumor samples for loss-of-function alterations in 15 genes with the FMI FoundationOne assay. Those genes were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L.
The most common mutations were in ATM and BRCA2. Only 1 patient in the experimental arm and 2 patients in the placebo arm had BRCA1 mutations in this study.
Toni K. Choueiri, MD:
The primary endpoint of PFS in the intention-to-treat (ITT) population was not met.17 The median PFS was 4.2 months with durvalumab plus olaparib vs 3.5 months with durvalumab plus placebo (HR: 0.94; 95% CI: 0.64-1.39). Exploratory subgroup analyses identified HRR status and Bajorin risk index as potentially associated with PFS.
Toni K. Choueiri, MD:
Among the 17 HRRm patients receiving durvalumab plus olaparib and 14 HRRm patients receiving durvalumab plus placebo, a prespecified secondary analysis showed a PFS benefit (HR: 0.18; 95% CI: 0.06-0.47).17 However, the absolute benefit was small at 5.6 months vs 1.8 months.
Toni K. Choueiri, MD:
In an exploratory analysis of median OS by HRR status, there was a signal for benefit in the HRRm subgroup but no benefit in the ITT population.17 For patients who received durvalumab alone, the HRRm subgroup had a median OS of only 5.8 months vs 13.7 months in the HRR wild-type subgroup. So, in addition to looking at HRR status as a predictive factor for PARP inhibitors, we must also remember how HRRm status negatively affects survival with single‑agent immune checkpoint inhibitors.
Toni K. Choueiri, MD:
There was no significant difference in response rates in the ITT population, but there was a numerical improvement with the combination, with an ORR of 28.2% with durvalumab plus olaparib vs 18.4% with durvalumab plus placebo.17 In the 17 patients with HRRm in the durvalumab plus olaparib arm, 6 patients (35.3%) had a response vs 0 out of 14 patients in the durvalumab plus placebo arm.
Toni K. Choueiri, MD:
Unsurprisingly, any-grade and grade 3/4 AEs were more common in the arm with the addition of olaparib to durvalumab.17 There were higher rates of anemia, fatigue, and GI AEs with the addition of olaparib. There was 1 death in the placebo arm due to anemia related to study drug.
Toni K. Choueiri, MD:
In the BAYOU trial, durvalumab plus olaparib did not significantly improve PFS vs durvalumab plus placebo as first-line treatment for patients with platinum-ineligible, unresectable, stage IV urothelial carcinoma.17
The preplanned secondary analysis observed a potential PFS benefit with durvalumab plus olaparib in the HRRm subgroup. Overall, the HRRm subgroup had a shorter OS regardless of treatment, consistent with a poor prognosis in this population. The safety profiles were consistent with known toxicities for each drug. The investigators suggested that PARP inhibition may have a role in treating metastatic urothelial cancer with HRRm, with further study warranted.
Dr. Petrylak, what do you think?
Daniel P. Petrylak, MD:
I am not very excited by these data, especially the data in all‑comers. I think a larger trial evaluating PARP inhibition would be reasonable in those with HRRm.
Toni K. Choueiri, MD:
I agree. I wish there were another way to bring PARP inhibitors into management of urothelial cancer.
Toni K. Choueiri, MD:
ATLANTIS is an ongoing adaptive, multicomparison phase II trial. At ASCO GU 2022, Crabb and colleagues18 presented data from the final analysis of the rucaparib comparison arm. This report compared maintenance rucaparib vs placebo in 40 patients with urothelial carcinoma (T4b and/or N1-3 and/or M1) who achieved stable disease, partial response (PR), or CR on first-line platinum‑based chemotherapy. Recruitment was discontinued after 40 patients were randomized due to COVID-19 emerging and data reported supporting maintenance avelumab in this setting.
As we discussed previously, the definition of biomarker positivity often differs between trials. In ATLANTIS, all patients were biomarker positive for DNA repair deficiency (DRD) based on a 15‑gene panel or known germline BRCA1/2 alteration.
The primary endpoint of the study is PFS, and secondary endpoints are OS, confirmed ORR, and safety. The statistical design was prospectively revised in February 2021 to have 85.4% power for a target HR: 0.5.
Toni K. Choueiri, MD:
DRD biomarker status was evaluated using somatic tumor testing of archival samples with FoundationOne NGS.18 DRD biomarker positivity was defined as meeting ≥1 of the following criteria: ≥10% genome-wide loss of heterozygosity, somatic alteration in 1 of 15 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L), or a known germline alteration in BRCA1 or BRCA2.
Of the 279 patients registered to ATLANTIS, 248 patients were prescreened for the rucaparib comparison, with 74 patients identified as DRD biomarker positive, and 40 patients ultimately randomized. Of those 40 patients, 22 (55%) had ≥10% loss of heterozygosity, 11 (27.5%) had a DRD gene altered, and 7 (17.5%) met both criteria.
Toni K. Choueiri, MD:
Baseline characteristics were balanced between arms.18 The median age in both arms was approximately 70 years.
Toni K. Choueiri, MD:
There was numerical improvement in PFS with maintenance rucaparib vs placebo, with a median of 35.3 vs 15.1 weeks, respectively.18 However, this did not translate into statistical significance, despite an HR: 0.53 (80% CI: 0.30-0.92; P = .07).
OS also numerically favored maintenance rucaparib, with a median OS that was not reached vs 72.3 weeks with placebo and an HR of 1.22. Again, this benefit was not statistically significant (80% CI: 0.62-2.38; P = .35)
The differences may have been more pronounced in a much larger study; unfortunately, this was an underpowered, negative trial.
Toni K. Choueiri, MD:
The safety data were consistent with previous data for rucaparib and other PARP inhibitors.18 Fatigue, nausea, rash, and increased alanine aminotransferase levels were all significantly more common in patients receiving rucaparib vs placebo.
Toni K. Choueiri, MD:
In the randomized phase II ATLANTIS trial, patients with DRD biomarker positivity who received maintenance rucaparib after platinum-based chemotherapy had numerically improved median PFS vs placebo (35.3 vs 15.1 weeks), but the benefit was not statistically significant (HR: 0.53; 80% CI: 0.30-0.92; P = .07).18
The safety profile of maintenance rucaparib was tolerable. The investigators concluded that the results support further study of PARP inhibitors in biomarker-selected patients with urothelial carcinoma.
Daniel P. Petrylak, MD:
I am an investigator on this next study, which was presented by Grivas and colleagues19 at ASCO GU 2022. This was an analysis of Cohort 3 of the international, open-label phase II TROPHY‑U-01 trial. Cohort 3 enrolled 41 patients with metastatic urothelial cancer to receive sacituzumab govitecan plus pembrolizumab following progression on platinum‑based chemotherapy. Patients were immune checkpoint inhibitor naive, had adequate creatinine clearance, adequate hepatic function, and no active brain metastases. Sacituzumab govitecan was administered on Day 1 and Day 8, and pembrolizumab was administered on Day 1 of 21-day cycles. Treatment continued until disease progression or unacceptable toxicity.
The primary endpoint of the study is investigator-assessed ORR, and key secondary endpoints are duration of response, PFS, OS, and safety.
Daniel P. Petrylak, MD:
At baseline, 28 patients (68%) had visceral metastases, with 12 patients (29%) having liver metastases.19 Looking at poor prognostic factors, 11 patients (27%) had 2 Bellmunt risk factors. Nearly half of patients had received prior neoadjuvant chemotherapy. The best response to prior systemic therapy in the metastatic setting was CR in 1 patient (2%), PR in 2 patients (5%), stable disease in 11 patients (27%), and progressive disease in 6 patients (15%).
Daniel P. Petrylak, MD:
The study met its primary objective, with ≥13 responses observed.19 The ORR was 34% with a best overall response of CR in 1 patient (2%), PR in 13 patients (32%), and stable disease in 11 patients (27%). At a medium follow-up of 5.8 months, the median PFS was 5.5 months (95% CI: 1.7 to not reached) and the median OS was not reached. The median duration of response was not reached.
Daniel P. Petrylak, MD:
As we can see in this waterfall plot, there were some patients who did not quite reach the threshold for PR.19 Tumor shrinkage was observed in 63% of the patients.
Daniel P. Petrylak, MD:
At the data cutoff, the longest treatment duration was approaching 14 months in a patient with a PR.19
Daniel P. Petrylak, MD:
At data cutoff, 13 patients (32%) remained on treatment whereas 28 patients (66%) had permanently discontinued.19 Disease progression was responsible for 21 discontinuations (51%), and AE was responsible for 1 discontinuation (3%) due to grade 2 altered general condition. The dose of sacituzumab govitecan was reduced due to TRAE in 16 patients (39%).
There were no new safety signals observed, and both sacituzumab govitecan and pembrolizumab were well tolerated. The most common AEs were diarrhea in 29 patients (71%) and nausea in 22 patients (54%). Grade ≥3 febrile neutropenia affected 4 patients (10%) who had no prior granulocyte colony-stimulating factor. Grade 3/4 TRAEs occurred in 59% of patients.
Daniel P. Petrylak, MD:
The combination of sacituzumab govitecan plus pembrolizumab resulted in an ORR of 34% in this cohort with metastatic urothelial cancer after progression on platinum-based chemotherapy.19 The study met its primary objective with ≥13 responses observed. After a median follow-up of 5.8 months, the median duration of response and median OS were not reached. The safety profile was manageable, and no new safety signals were observed.
Follow-up and biomarker assessment are ongoing, Results from this analysis support further study of sacituzumab govitecan plus immune checkpoint inhibitor in earlier lines and post-platinum for metastatic urothelial carcinoma. Additional combination regimens with sacituzumab govitecan are under evaluation in other TROPHY-U-01 cohorts and in the phase III TROPiCS-04 trial (NCT04527991).
I found these results intriguing. This patient population differs from most cohorts in the EV-103 trial in that they have more advanced disease and had received platinum-based chemotherapy. Thus, data cannot be directly compared.
Dr. Choueiri, what are your thoughts?
Toni K. Choueiri, MD:
The safety data are okay, but we need more follow-up. The median duration of response is not yet reached, which is great. The study meeting the primary endpoint of ORR was also great. But the single-agent activity of sacituzumab govitecan is similar to what was observed in this trial. From KEYNOTE-045, which also enrolled patients who progressed following platinum-based chemotherapy, we know that pembrolizumab monotherapy has an ORR of 21.1%, so I was expecting a higher response rate with the addition of sacituzumab govitecan.20 Follow-up will be important to see what happens with the ORR over time.
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