March 2020 Edition Vol.11, Issue 3

Wins at ASCO GU 2020

By Christina Bennett, MS

The 2020 ASCO Genitourinary Cancers Symposium provided encouraging results from several clinical studies, including a platinum-free regimen in urothelial carcinoma (Abstract 441), long-term results for nivolumab and ipilimumab in renal cell carcinoma (Abstract 609), and a first look at a novel agent in kidney cancer (Abstract 611). In addition, positive results from the BLASST-1 (Abstract 439), COSMIC-021 (Abstract 139), and NEODURVARIB (Abstract 542) trials were reported.

Platinum-free regimen in urothelial carcinoma

The antibody-drug conjugate, enfortumab vedotin, in combination with pembrolizumab appeared to have durable clinical activity as a first-line treatment in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

Updated response data from the EV-103 trial showed that of the 45 patients who received the combination, 16% (7 patients) had a complete response (CR) while 58% (26 patients) had a partial response (PR), totaling to a 73% overall response rate (ORR).  At follow-up of 10.4 months, the median duration of response (DOR) for patients who received the drug combination had not yet been reached; 12-month DOR rate was 54% (95% CI, 27.4 – 74.1). Median progression-free survival (PFS) was 12.3 months and the median overall survival (OS) had not yet been reached. 

One patient died as a result of treatment and 6 patients discontinued due to treatment-related adverse events (TRAEs), with peripheral sensory neuropathy being the most frequent AE (3 patients).

“It looks like these outcomes are durable at this time,” said David Quinn, MD, associate professor of medicine, USC Norris Comprehensive Cancer Center. 

To confirm these findings, a pivotal phase 3 study is about to begin. 

View an interview with Dr. Quinn on the EV-103 trial: 

 

Longest follow-up data in RCC: CheckMate 214 

Four-year follow-up data from CheckMate 214 showed that first-line treatment with nivolumab plus ipilimumab continued to have superior clinical benefit compared with sunitinib alone in intermediate- and poor-risk patients with advanced renal cell carcinoma (RCC).

These long-term follow-up data are what “really distinguishes” the combination from the other agents, said Bradley McGregor, MD, Clinical Director, Dana Farber Cancer Institute.

Patients with intermediate- and poor-risk disease who received combination therapy (n=425) had a significantly higher confirmed response rate than those who received sunitinib (n=422); 42% vs 25%, respectively, (P<0.001) as well as CR rate (10% vs 1%, respectively). At 42 months minimum follow-up, median OS for the combination arm was approximately 20 months longer than the sunitinib arm (47.0 months vs 26.6 months, respectively; [HR=0.66; 95% CI, 0.55-0.80; P<0.0001]). 

View an OBR interview with Dr. McGregor on the CheckMate 214 trial: 

 

Novel agent shows clinical activity in RCC

The novel oral agent, MK-6482, showed clinical activity in 55 heavily pretreated patients with advanced clear cell RCC in a phase 1/2 trial. MK-6482 is the first therapeutic that targets hypoxia-inducible factor 2a (HIF-2a). 

No CRs were seen, and 13 patients had PRs, translating to an ORR of 24%. Responses were seen in 2 of 5 patients (40%) with favorable-risk disease, 10 of 40 (25%) with intermediate-risk disease, and 1 of 10 (10%) with poor-risk disease. The overall disease control rate (DCR) was 80%. Median DOR had not yet been reached and 16 patients (29%) remained on treatment after 12 months. Median PFS was 11 months for the overall study population.

Safety data revealed two on-target toxicities: anemia and hypoxia. Anemia was the most common adverse event, with 49% of patients having grade 1 or 2 and 26% having grade 3. Grade 1 or 2 hypoxia occurred in 11% of patients and grade 3 in 15%. 

“Overall it’s relatively well tolerated with low cessation rates,” said Dr. Quinn. Two patients (4%) discontinued treatment as a result of treatment-related hypoxia. 

A randomized phase 3 trial is underway to evaluate MK-6482 in previously treated patients with advanced clear cell RCC.

View an OBR interview with Dr. Quinn on the phase 1/2 MK-6482 trial: 

 

BLASST-1 trial launches immunotherapy in neoadjuvant bladder cancer

The single-arm, phase 2 BLASST-1 trial met its primary endpoint, showing that the addition of nivolumab to gemcitabine and cisplatin before cystectomy led to a pathologic response in 27 of 41 patients (66%) with muscle-invasive bladder cancer. In addition, 20 patients (49%) had a pathologic complete response.

Matthew Galsky, MD, professor of medicine at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, pointed out that pathologic response rate is not consistently defined in studies and clinical stage at baseline also differs, making it difficult to compare these results to those of other studies. In this study, pathologic response was defined as staging below pT2N0 and most patients (90%) had T2N0 stage disease. In contrast, pathologic complete response, which the study defined as pT0 or pTis, has been defined a bit more consistently across trials and the pathologic complete response shown in this study is encouraging, he noted. 

No delays to cystectomy were seen with the receipt of nivolumab and chemotherapy and PD-L1 expression did not appear to correlate with response, with similar response rates among patients with PD-L1 positive tumors and patients with PD-L1 negative (67% vs 71%). The most common grade 3 or 4 events were anemia (7%) and neutropenia (7%).

“The side effect profile is similar to that with chemotherapy plus immune checkpoint blockade regimens in the metastatic setting,” said Dr. Galsky.

The phase 3 ENERGIZE trial in underway and will evaluate neoadjuvant chemotherapy with or without nivolumab in patients with muscle-invasive bladder cancer. 

 

Stars align for cabozantinib and atezolizumab 

In the phase 1b COSMIC-021 study, median follow-up of 12.6 months for cabozantinib plus atezolizumab elicited a 32% ORR among 44 patients with metastatic castration-resistant prostate cancer (mCRPC). This is in contrast to the low response rate that was previously seen when either agent was used alone: 5% for cabozantinib; 0% for atezolizumab.1,2 

Tanya Dorff, MD, associate clinical professor, City of Hope, described the ORR as “pretty striking.” 

Responses included 2 confirmed CRs (4.5%) and 12 confirmed PRs (27%), with a DCR of 80%. Clinical activity did not appear linked to PD-L1 expression, according to preliminary data.

Overall, 59% of patients had a grade 3 or 4 TRAE and 39% of patients had dose reduction for cabozantinib due to adverse events. One patient died from dehydration, which was considered a TRAE. 

A phase 3 trial to evaluate the combination in patients with mCRPC is being planned. 

View an OBR interview with Dr. Dorff on the COSMIC-021 study: 

 

Chemotherapy-free regimen shows activity in bladder cancer

Neoadjuvant durvalumab plus olaparib show clinical activity in 29 patients with resectable muscle-invasive bladder cancer, preliminary data from the single-arm phase 2 NEODURVARIB trial showed. 

Half of patients achieved a pathological complete response and toxicity was similar to that typically seen with standard of care chemotherapy. The most common grade 3 adverse events were infection (18.5%) and wound evisceration (7.4%), and the most common grade 4 adverse events were septic shock (3.7%), hemorrhage (3.7%), and wound evisceration (3.7%).

“Overall, it looks like this is a fairly well tolerated treatment that could be a good alternative to chemotherapy,” said Yung Lyou, MD, PhD, medical oncologist at City of Hope. However, he cautioned that the sample size is small and whether the patients evaluated in this trial are “good candidates” for immunotherapy is unclear. 

Olaparib is typically given to patients with tumors that are positive for homologous recombination deficiency (HRD), the status of which was unknown for this study population because HRD status was not part of the trial eligibility criteria.


References

  1. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412-419.
  2. Kim JW, Shaffer DR, Massard C, et al. A phase Ia study of safety and clinical activity of atezolizumab (atezo) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2018;36(6): suppl 187.

Liquid Biopsy Gains at GU 2020

At ASCO GU 2020, the prospect of liquid biopsies was favorable for RCC, bladder cancer, and prostate cancer. The techniques used ran the gamut—circulating tumor cells, cell-free DNA, circulating tumor DNA—as did the applications explored—detecting biomarkers, selecting the right patient for treatment, monitoring response, and predicting survival. For example:

  • A bladder cancer study indicated that the detection of FGFR2/3 genomic alterations in cell-free DNA could identify candidates for erdafitinib (Abstract 565). 
  • For patients with metastatic castration-resistance prostate cancer (mCRPC), a study showed the alterations detected in circulating tumor DNA could be prognostic for survival (Abstract 110). 
  • Circulating tumor cell profiling could provide prognostic information for patients with CRPC treated with cabazitaxel (Abstract 154).
  • A study in variant histology renal cell carcinoma found that high levels of immunosuppressive cytokines and certain immune cells predicted worse survival, warranting further evaluation (Abstract 740). 

“I think it’s going to play a huge role going forward,” said Oliver Sartor, MD, professor of medicine and urology, Tulane University School of Medicine, about liquid biopsy. “It’s a great area and a burgeoning area. We need to learn more.”

View an OBR interview with Dr. Sartor on liquid biopsy: 

 

 

 

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