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At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2016), held June 3 to 7 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Associate Editor Robert Dreicer, MD, MS, FACP, FASCO, reviews key presentations on new genitourinary cancer therapies. All meeting abstracts can be viewed in the ASCO meeting library).
The anti–PD-L1 inhibitor atezolizumab was approved by the FDA in May of this year based on data from cohort 2 of the IMvigor210 study (abstract 355), which demonstrated significant activity in platinum-refractory patients with locally advanced and metastatic urothelial cancer. For patients with poor renal function or compromised performance status, therapy options are problematic, given that evidence of a survival benefit with carboplatin/gemcitabine, a community standard, is lacking.
Balar and colleagues conducted a primary analysis of cohort 1 of the IMvigor210 study (abstract LBA4500) to evaluate the role of atezolizumab in 119 chemotherapy-naive patients with advanced urothelial cancer who were cisplatin-ineligible, defined by renal insufficiency (glomerular filtration rate [GFR] >30 but <60 mL/min), hearing impairment, ≥G2 peripheral neuropathy, or performance status of ≥2. This population was representative of this disease state, as 21% were ≥80 years old, 70% had GFR between 30 and 60 mL/min, and 66% had visceral metastases.
Responses were seen irrespective of PD-L1 expression. The overall objective response rate was 24%: 7% achieved complete response, and 17% achieved partial response. At a median follow-up of 14.4 months, overall survival was 14.8 months, and 57% of patients were alive at the 1-year landmark. Therapy was well tolerated; most toxicities were grade 1 or 2. Fatigue was the most common adverse event. Six percent of patients experienced a grade 3 or 4 immune-mediated event. There was one therapy-related death.
After 30 years of limited progress with cytotoxic therapy, these finding and others presented at the meeting highlight the beginning of a paradigm shift toward immunomodulatory therapy. Ongoing phase III trials will provide additional data to guide therapeutic decisions in this difficult-to-manage disease subset.
Following the FDA approval of cabazitaxel in 2010 for men with metastatic castration-resistant prostate cancer (mCRPC) after progression on docetaxel, the international, randomized, open-label, phase III FIRSTANA study by Sartor and colleagues (abstract 5006) was developed in response to an FDA postmarketing requirement.
A total of 1168 mCRPC patients with progression after docetaxel and performance status 0 to 2 were randomized to receive cabazitaxel (20 or 25 mg/m2) or docetaxel (75 mg/m2), all with prednisone at standard doses. The average age of patients was 68 to 69 years, and 95% had performance status of 0 or 1. Patients in all three groups averaged about 10 cycles of treatment.
Overall survival (the primary endpoint) of all three groups overlapped in the 24- to 25-month range. More grade 3 or 4 and serious treatment-emergent adverse events occurred in the cabazitaxel 25 mg/m2 arm. Rates of grade 3 or 4 febrile neutropenia in the docetaxel, cabazitaxel 20 mg/m2, and 25 mg/m2 arms were 8.3%, 2.4%, and 12%.
This trial provides an abundance of practice-informing data regarding the role of taxanes in mCRPC, in that cabazitaxel, irrespective of dose, is not more active than docetaxel in the frontline mCRPC setting. Regarding the optimal dose of cabazitaxel, these results support the findings of the PROSELICA study (abstract 5008), also presented at this meeting, which demonstrated similar activity of cabazitaxel at either the 20 mg/m2 or 25 mg/m2 dose, with a more favorable toxicity profile of 20 mg/m2, which should now become the standard.
Earlier this year, the FDA approved cabozantinib — a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL — for advance renal cell cancer patients with disease progression following initial anti-angiogenic therapy. This approval was based on a phase III trial demonstrating significant improvement in progression-free survival (PFS) for patients treated with cabozantinib versus everolimus.
In the phase III METEOR study (abstract 4506), Choueiri and colleagues randomized 658 renal cell cancer patients with a component of clear cell cancer to receive everolimus at 10 mg/day or cabozantinib at 60 mg/day. The median age was 62 to 63 years, most patients had favorable or intermediate risk, and about 30% of patients had received >2 prior VEGFR TKIs.
PFS was longer with cabozantinib than with everolimus (7.4 vs. 3.9 months; P<0.0001), as was overall survival (21.4 vs. 16.5 months; P=0.0003). Everolimus toxicity was similar to that seen in clinical practice; diarrhea, fatigue, nausea, decreased appetite, hand-foot syndrome, and hypertension were common with cabozantinib.
Cabozantinib now joins nivolumab in demonstrating the potential to prolong overall survival in the second-line setting for renal cell cancer. With the very recent approval of lenvatinib in combination with everolimus for patients in this setting, a wide variety of management options now exist. The optimal sequencing and use of these agents is currently undefined. However, there are differences in objective response rates and toxicity profiles that can help inform these decisions.