Adjuvant Axitinib Misses Primary Endpoint in Phase III RCC Trial

Mace Rothenberg, MD

Mace Rothenberg, MD

According to findings from the phase III ATLAS trial, disease-free survival (DFS) was not extended with adjuvant axitinib (Inlyta) versus placebo for patients at high risk of recurrent renal cell carcinoma (RCC) after nephrectomy.

Pfizer, the manufacturer of the VEGFR tyrosine kinase inhibitor (TKI), announced that an independent data monitoring panel has recommended the trial be stopped, based on it missing the primary DFS endpoint. Detailed findings from the trial will be presented at an upcoming medical conference, according to Pfizer.

“We are disappointed by the outcome of this study as we had hoped the efficacy that Inlyta has demonstrated as a second-line treatment in patients with advanced RCC would carry over to patients with earlier stage disease, where it would delay or prevent disease relapse. That goal was not achieved,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

“We will conduct additional analyses on the data that may provide insight into this result. Studies evaluating Inlyta in combination with immune checkpoint inhibitors for patients with a variety of advanced stage cancers, including RCC, will continue,” added Rothenberg.

Another VEGFR TKI, sunitinib (Sutent), previously demonstrated success in this setting. In results from the phase III S-TRAC trial, which were presented at the 2016 ESMO Congress and published in theNew England Journal of Medicine,^1,2adjuvant sunitinib prolonged DFS by 1.2 years compared with placebo following nephrectomy for patients with high-risk clear cell RCC. Based on these findings, the FDA approved sunitinib in November 2017 for use in this setting.

After a median follow-up of 5.4 years in the S-TRAC trial , the median DFS was 6.8 years in the sunitinib arm compared with 5.6 years with placebo (HR, 0.76; 95% CI, 0.59-0.98;P= .03). In higher risk patients, the median DFS was 6.2 versus 4.0 years for sunitinib and placebo, respectively (HR, 0.74; 95% CI, 0.55-0.99;P= .04). Grade 3/4 AEs were experienced by 63.4% of patients in the sunitinib group compared with 21.7% in the placebo arm.

The study randomized 615 patients with clear cell RCC to receive sunitinib (n = 309) or placebo (n = 306). Patient characteristics were well balanced between the arms. The median age of patients in the sunitinib arm was 57 years, and most were males (71.8%). Most patients had an ECOG performance score of 0 (73.8%).

Overall, 90.6% of those in the sunitinib arm had a stage 3 tumor, with no nodal involvement and no metastasis. Of these patients, 37.2% were considered low-risk (any Fuhrman grade and ECOG score of 0 or Fuhrman grade 1 and ECOG score of ≥1) and 53.4% were high-risk (Fuhrman grade ≥2 and ECOG score of ≥1).

Sunitinib was administered at 50 mg daily for 4 weeks followed by 2 weeks without treatment. One dose reduction was allowed in the study, to 37.5 mg per day. Overall, more than half of patients (54.2%) were able to maintain treatment with the starting dose of 50 mg per day. The median daily dose was 45.9 mg.

After 3 years, 64.9% of those in the sunitinib group were alive and remained disease-free compared with 59.5% in the placebo arm. At 5 years, the DFS rate was 59.3% with sunitinib versus 51.3% for placebo. Median overall survival findings were not yet mature at the time of the analysis; however, the hazard ratio between the two arms for survival was 1.01 (95% CI, 0.72-1.44;P= .94).

The investigator assessed median DFS in the sunitinib arm was 6.5 years compared with 4.5 years with placebo (HR, 0.81; 95% CI, 0.64-1.02;P= .08). In higher risk patients, the median DFS by investigator assessment was 5.9 versus 3.9 years for sunitinib and placebo, respectively (HR, 0.76; 95% CI, 0.58-1.01;P= .06).

Treatment-emergent AEs were experienced by 99.7% of patients treated with sunitinib versus 88.5% in the placebo arm. Treatment-emergent AEs by investigator assessment occurred in 98.4% of those treated with sunitinib versus 75.7% with placebo. AEs led to discontinuation for 28.1% of patients in the sunitinib arm versus 5.6% of those in the placebo group.

The most common AEs in the sunitinib arm were diarrhea (56.9%), palmar—plantar erythrodysesthesia (50.3%), hypertension (36.9%), fatigue (36.9%), and nausea (34.3%). The most common grade 3/4 AEs were palmar–plantar erythrodysesthesia (16%), neutropenia (8.5%), hypertension (7.8%), and thrombocytopenia (6.2%). The rate of serious adverse events AEs was similar for sunitinib (21.9%) versus placebo (17.1%).

References:

1. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy [published online October 10, 2016].N Engl J Med.DOI: 10.1056/NEJMoa1611406.
2. Ravaud A, Motzer RJ, Pandha HS, et al. Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA11.

The global, multicenter, double-blind phase III ATLAS study (NCT01599754) randomized 724 patients at high risk for RCC recurrence after nephrectomy to either adjuvant axitinib at 5 mg twice daily or placebo. Patient received treatment for 1 to 3 years. Pfizer noted in its statement that there were no new safety signals, with adverse events (AEs) similar to previously reported results with axitinib in patients with advanced RCC.