ASCO 2020: Pathbreaking trials in genitourinary cancer for Indian Oncologists: Dr. Akhil Kapoor
M3 India Newsdesk Jun 10, 2020
Dr. Akhil Kapoor picks notable trials in genitourinary cancer presented at this year's American Society of Clinical Oncology (ASCO) 2020 live virtual meeting, commenting on how they will affect practice among Indian Oncologists.
Update of Keynote-426
With the availability of updated data of CheckMate 214 (in GU ASCO 2020), the combination of Nivolumab and ipilimumab (N+I) became the preferred combination for intermediate/high risk ccRCC. However, due to update of P+A in this ASCO, it appears that the combination of P+A has regained its throne. Few important points in favor of P+A are as follows.
The PFS curves for N+I start to separate at 9 months while for P+A, it is as early as 3 months. Another way of understanding this difference is that progressive disease was the best response in 25% patients in N+I study while this data was 14.6% for P+A. Thus, for patients in which there is a concern for rapid deterioration due to high burden of disease that may prevent reaching effective second-line therapy, P+A appears to be a better choice.
Another important way of selecting between the two therapies can be the PD-L1 expression. If PD-L1 is <1%, there is higher chances of failure of N+I. An important concern with N+I being the higher rate of immune related adverse effects (irAEs) with N+I necessitating the use of steroids in 60% of the patients while only 10% patients of P+A had grade 3 or higher irAEs. It should be noted that Ipilimumab is not yet available in India and with this update, we can rest assured that we are still providing the best possible treatment if P+A can be afforded by the patient.
Plimack et al. presented a follow-up of the Keynote-426 study which compared Pembrolizumab plus axitinib (P+A) versus Sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC). The superiority of P+A over Sunitinib was maintained, with an overall response rate (ORR) of 60% versus 40% and a complete response (CR) rate of 8.8% versus 3% for P+A versus Sunitinib, showing that this remains a preferred regimen for patients with advanced sporadic RCC. The corresponding two-years overall survival (OS) rates were 74% and 66%. In the IMDC favourable risk, the OS and PFS were similar, however ORR was 70% versus 50% favouring P+A. For intermediate/high risk, there was clear benefit in terms of ORR, PFS, and OS.
Lenvatinib plus Pembrolizumab for patients progressed on immunotherapy for metastatic RCC
This is one of the best responses in immunotherapy refractory patients, and supports further development of this combination as a later-line therapy in advanced RCC. It should be noted that Lenvatinib is already approved in combination of Everolimus post progression on VEGF-directed therapy.
Lee et al. presented phase II trial of Lenvatinib (Len) plus Pembrolizumab (P) for disease progression after PD-1 immune checkpoint inhibitor in metastatic ccRCC. In this 104-patient study, Len was used at a dose of 20 mg OD and P 200 mg, 3-weekly. With the combination of Len+P, the ORR was 51%, PFS was 11.7 months, and median duration of response was 9.9 months.
Bevacizumab plus Erlotinib in papillary RCC
These are groundbreaking data for patients with HL-related RCC. It should be noted that for patients with sporadic papillary RCC, a phase III randomised trial SUNIFORCAST is comparing Nivolumab plus Ipilimumab verus Sunitinib. Meanwhile, these patients can be offered immunotherapy (Nivolumab or Pembrolizumab) as first-line therapy if affordable based on phase II non-randomised data.
In a phase II study by Srinivasan et al., Bevacizumab and Erlotinib combination was used in patients with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary RCC. HLRCC is an autosomal dominant condition where individuals develop cutaneous leiomyomas, uterine leiomyomas, and type 2 papillary RCC. The ORR was 64% in the HLRCC cohort (n=43) and 37% in the sporadic cohort (n=40). The median PFS was 21.1 months in the HLRCC cohort and 8.7 months in the sporadic cohort.
Savolitinib in MET-driven papillary RCC
Savolitinib demonstrated favorable efficacy and safety compared with Sunitinib in this small study. Since Savolitinib is presently not available in India, the compassionate access may be attempted for suitable patients.
Another study compared Savolitinib (a highly selective MET-TKI) with standard-of-care Sunitinib in MET-driven papillary RCC (type I).
TheraP Study
LuPSMA is a radiolabeled small molecule that delivers therapeutic β-radiation to PSMA-expressing tumours. For men with mCRPC after Docetaxel and anti-androgen therapy, LuPSMA demonstrated a greater PSA50 response over Cabazitaxel with a better toxicity profile. It should be noted that all patients will not qualify for LuPSMA, due to low or discordant PSMA activity compared with FDG PET. PFS data is immature until now but appears promising. OS data is not yet out from either this study and also from another phase III study named VISION which randomised patients to either LuPSMA plus best supportive care (BSC) or BSC alone. The OS data, if favourable will make this treatment as standard of care for heavily pre-treated mCRPC patients. In the clinic, we have already started to use this therapy in selected patients.
Hofman et al. presented TheraP study which is a randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) versus Cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after Docetaxel. mCRPC patients with high PSMA expression (n=200) were randomly assigned 1:1 to LuPSMA or Cabazitaxel. A PSA response rate of greater than 50% reduction (PSA50-RR) was seen in 66% of patients in the LuPSMA group versus 37% in the Cabazitaxel group. PSA-PFS was significantly improved in the LuPSMA group. There were relatively fewer grade 3/4 adverse events in the LuPSMA group.
Neoadjuvant Gemcitabine and Pembrolizumab for locally advanced urothelial cancer
The current standard of care for localised muscle-invasive bladder cancer involves Cisplatin-based chemotherapy prior to cystectomy. The pCR rate to this therapy is roughly 20 to 30%. However, upto 30 to 40% of patients with MIBC are not candidates for Cisplatin-based therapies, most commonly due to poor renal functions, besides due to baseline hearing loss or neuropathy. It should be noted that ABACUS and PURE 01 studies (phase II) have already reported high pCR rates (32-42%) with neoadjuvant immunotherapy alone. It is unclear presently as to how we will select patients for neoadjuvant chemo-immunotherapy combination.
Interim results from the Cisplatin-ineligible cohort of GU14-188 were presented. This study replaces cisplatin with Pembrolizumab in combination with Gemcitabine as neoadjuvant therapy for patients with muscle-invasive bladder cancer (MIBC). Five doses of neoadjuvant Pembrolizumab were given starting on C1D8 of Gemcitabine, which was given on days 1, 8, and 15 of a 28-day cycle (x 3 cycles). The primary endpoint of the study was pathologic muscle-invasive response rate (pCR) defined as ≤pT1N0. The primary endpoint was reached in 52% of patients and a pCR was achieved and 45.2% of patients. The 12-month relapse-free survival was 67% and the 12-month disease-specific survival was 94%, with OS of 88.4% at 12 months. Of note, 11% (4/37) of patients developed grade 3 immune-related adverse event which led to treatment discontinuation in 3 of the patients.
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
The writer, Dr. Akhil Kapoor, MD, DM, ECMO is working as an Assistant Professor in the Department of Medical Oncology, Mumbai. He has more than 100 publications in national and international peer-reviewed journals. He also has a keen interest in clinical research and in contributing to the advancement of patient care in Oncology.
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