NEO-BLADE
Nintedanib, an orally available triple receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-3, and PDGFR α and β, has shown efficacy against lung and pancreatic tumors in animal models. Nintedanib plus docetaxel produced an objective response rate of 48% in a recent human study (VARGADO) of patients whose non-small cell lung cancer had progressed on immunotherapy.
Syed A. Hussain, MD, explained that the NEO-BLADE study compares nintedanib or placebo plus chemotherapy (gemcitabine and cisplatin) in locally advanced muscle-invasive bladder cancer. The primary endpoint is the rate of pathologic complete response.
The slides below show the study design and baseline characteristics of the 120 study participants. Most were men with T2 disease and an ECOG performance status of 0.
Rates of complete pathologic response were 36.8% with nintedanib plus chemotherapy vs. 31.7% with placebo plus chemotherapy. Because this difference was not statistically significant, the study missed its primary endpoint. However, improvements in progression-free survival (PFS) and OS were observed. Rates of PFS at 12 months were 89% with nintedanib plus chemotherapy vs. 74.1% with placebo plus chemotherapy. Twelve-month OS rates were 96% vs. 82%.
Rates of complete pathologic response were 36.8% with nintedanib plus chemotherapy vs. 31.7% with placebo plus chemotherapy. Because this difference was not statistically significant, the study missed its primary endpoint. However, improvements in progression-free survival (PFS) and OS were observed. Rates of PFS at 12 months were 89% with nintedanib plus chemotherapy vs. 74.1% with placebo plus chemotherapy. Twelve-month OS rates were 96% vs. 82%.
Nintedanib was associated with an increase in toxicities, including a rate of grade 3 toxicities of 40% vs. 19% in the control arm. Rates of thrombosis were approximately 20% in each arm.
While adding nintedanib to chemotherapy did not significantly improve clinical complete response (38.6% vs 39.7%) or pathologic complete response (51% vs. 44%), the PFS and OS benefits are encouraging. One limitation of this study was that decisions on definitive therapy were not planned before treatment. Discussing local treatment options after chemotherapy might have biased the pT0 results.
BLASST-1
The phase II BLASST-1 trial evaluates the efficacy and safety of nivolumab plus standard-of-care gemcitabine/cisplatin chemotherapy in patients with muscle-invasive bladder cancer. Study participants are fit for chemotherapy, T2-T4a, N≤1 M0, and planning radical cystectomy. As in NEO-BLADE, the primary endpoint is complete pathologic response (<pT2N0); secondary endpoints include safety and PFS. At the 2019 International Bladder Cancer Network (IBCN) meeting, investigators reported initial results including a pathologic response in 24 of 29 patients. At ASCO GU 2020, Dr. Shilpa Gupta, MD, presented results for an expanded cohort of 41 patients.
Baseline characteristics are shown below.
In all, 66% of patients achieved a complete pathologic response, which included patients with baseline N1 disease. This rate compares favorably to that seen with gemcitabine/cisplatin or MVAC (40% to 50%).3
There were no treatment-emergent deaths, and most adverse events were related to chemotherapy. Pathologic response did not correlate significantly with PD-L1 status.
Importantly, adding nivolumab to chemotherapy did not delay surgery or lead to unexpected surgical complications.
Fascinating biomarker results were presented for two patients: a complete responder with a Claudin-low signature, high immune infiltration, and basal marker expression, and a non-responder (pT3N2) with high stromal infiltration and modest luminal marker expression
In conclusion, NEO-BLADE and BLASST-1 provide evidence that adding a tyrosine kinase inhibitor (nintedanib) or an immune checkpoint inhibitor (nivolumab) to cisplatin/gemcitabine chemotherapy may improve long-term outcomes. A randomized placebo-controlled phase III study is needed to confirm these encouraging results. It also is important to carefully consider clinical and financial toxicities as well as time to surgery when adding any agent to the current standard of oncologic care.
Presented by: Andrea Necchi, MD, Fondazione IRCC Istituto Nazionale dei Tumori, Milan, Italy
Written by: Jason Zhu, MD. Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
References:
- Vale C, Collaboration ABCM-a. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. The Lancet 2003;361:1927-34.
- Zargar H, Espiritu PN, Fairey AS, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. European urology 2015;67:241-9.
- Lee FC, Harris W, Cheng HH, et al. Pathologic response rates of gemcitabine/cisplatin versus methotrexate/vinblastine/adriamycin/cisplatin neoadjuvant chemotherapy for muscle invasive urothelial bladder cancer. Advances in urology 2013;2013.