Barcelona, Spain (UroToday.com) First-line metastatic urothelial carcinoma treatment includes cisplatin or carboplatin-based chemotherapy or checkpoint inhibitors, depending on patient eligibility and PD-L1 status. Approximately 50% of patients are platinum ineligible and they may receive inferior carboplatin-based regimens. In July 2018, the FDA and EMA revised the first-line label for atezolizumab and pembrolizumab based on IMDC assessments. IMvigor130 is a phase 3, global, multicenter, randomized, partially blinded study evaluating atezolizumab (anti–PD-L1) alone or with platinum-based chemotherapy vs placebo + platinum-based chemotherapy in untreated metastatic urothelial carcinoma. At the ESMO 2019 Presidential session, Dr. Enrique Grande presented the final PFS and interim overall survival (OS) results for IMvigor130.
IMvigor130 enrolled 1,213 platinum-based chemotherapy-eligible patients with metastatic urothelial carcinoma. Patients were randomized 1:1:1 to Arm A (atezolizumab + platinum-based chemotherapy [gemcitabine + either cisplatin or carboplatin]), Arm B (atezolizumab) or Arm C (placebo + platinum-based chemotherapy). Stratification factors were PD-L1 status on tumour-infiltrating immune cells (IC; IC0 vs IC1 vs IC2/3), Bajorin risk factors/liver metastases (0 vs 1 vs 2 or patients with liver metastases) and investigator-specified platinum-based chemotherapy (gemcitabine + carboplatin vs gemcitabine + cisplatin). Based on the publication of several trials during the enrollment period, there were several key protocol amendments:
- Initially, there were two arms with a 2:1 randomization schema for cisplatin-ineligible patients only and there was no monotherapy arm (n=129)
- Amendment to three arms with a 1:1:1 randomization schema for cisplatin eligible and ineligible patients with a monotherapy arm (n=1,078). The rationale was that IMvigor210 results provided proof-of-concept for testing atezolizumab monotherapy and including cisplatin-eligible patients
- Amendment to using monotherapy only for PD-L1 IC2/3 patients (n=6). The rationale was that the IMDC recommended a change based on early assessment of the atezolizumab monotherapy arm
Gemcitabine 1000 mg/m2 IV was given on Day 1 and Day 8, carboplatin AUC 4.5 IV or cisplatin 70 mg/m2 IV on Day 1 and atezolizumab/placebo or atezolizumab 1200 mg IV on Day 1 of each 3-week treatment cycle. Tumors were assessed at baseline and every 9 weeks until investigator-assessed progressive disease per RECIST 1.1 or other events. The co-primary efficacy endpoints were investigator-assessed PFS and OS (Arm A vs C) and OS (Arm B vs C) per RECIST 1.1.
The IMvigor130 study design:
With a median follow-up of 11.8 months, the median PFS was 8.2 months in Arm A vs 6.3 months in Arm C (HR 0.82, 95% CI 0.70-0.96; p = 0.007):
The PFS benefit of combination therapy was robust across most subgroups. The comparison of OS did not cross the prespecified interim efficacy boundary, with a median of 16.0 months in Arm A and 13.4 months in Arm C (HR 0.83, 95% CI 0.69-1.00; p = 0.027). For Arm B vs C, the median OS was 15.7 months and 13.1 months, respectively (HR 1.02, 95% CI 0.83-1.24), for ITT pts and not estimable and 17.8 months, respectively (HR 0.68, 95% CI 0.43-1.08), for PD-L1 IC2/3 patients.
The ORR was 47% for Arm A, 23% for Arm B and 44% for Arm C. The CR rates were 13% for Arm A, 6% for Arm B, and 7% for Arm C. Adverse events that led to treatment withdrawal occurred in 34% of patients in Arm A, 6% of patients in Arm B, and 34% of patients in Arm C.
Dr. Grande concluded his presentation of the IMvigor130 with the following take-home messages:
- IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in PFS over standard of care in the first line metastatic urothelial carcinoma setting
- At this interim analysis, clinically meaningful improvement in OS was observed with atezolizumab + platinum/gemcitabine vs placebo + platinum/gemcitabine but did not cross the pre-specified interim efficacy boundary
- The OS benefit of atezolizumab monotherapy vs placebo + platinum/gemcitabine was greater in PD-L1 selected patients (IC2/3) than in ITT patients, although not formally tested
- Atezolizumab + platinum/gemcitabine was well tolerated, with a safety profile consistent with each individual agent
- The results from IMvigor130 support atezolizumab + platinum/gemcitabine as an important new treatment option for patients with untreated metastatic urothelial carcinoma
Clinical trial identification
Presented by: Enrique Grande, MD, Medical Oncologist and Head of the Medical Oncology Service at MD Anderson Cancer Center Madrid, Madrid, Spain
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain