Although a prior study examining sunitinib, S-TRAC (sunitinib as adjuvant treatment for patients at high risk of recurrence of renal cell carcinoma following nephrectomy; ClinicalTrials.org Identifier: NCT00375674), showed that the medication conferred a “clinically meaningful 24% reduction in risk of occurrence of a disease-free survival event” compared with placebo (P = .03) for patients with locoregional renal cell carcinoma at high risk for tumor recurrence after nephrectomy,1 another, earlier study (ASSURE; ClinicalTrials.org Identifier: NCT00326898) found there was no treatment advantage in RCC for adjuvant therapy with sunitinib or sorafenib when compared to placebo.2
Not only does sunitinib as an adjunctive therapy have mixed study results, but new data on sunitinib as an adjunctive therapy in patients with a high risk of recurrence of renal cell carcinoma (RCC) demonstrated that treatment with the drug was also linked to a worse health-related quality of life (HRQoL) compared with placebo.
“Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects,” wrote the authors of the article, which appeared in Annals of Oncology.3
Study participants were randomly assigned to receive sunitinib 50 mg daily or placebo. In the event of adverse events (AEs), patients being administered sunitinib were allowed to have their doses reduced to a minimum of 37.5 mg, delay doses, or discontinue treatment. Patients reported their AEs and HRQoL scores were evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
Adverse events occurred in a median of approximately 1 month following initial treatment. Despite the fact the researchers reported that approximately 87% of AEs resolved or were resolving 28 days following treatment, and nearly 41% of AEs leading to treatment discontinuation were either grade 1 or grade 2, there were at least 11 cases in which these adverse events were considered lasting or irreversible. Dosage alterations were first made at a median of 2.9 months, with dose interruption occurring at a median of 3 months.
The frequency of AEs in the sunitinib and placebo arms was 21.9% and 17.1%, respectively — but the AEs were the driving force behind treatment discontinuation in 28.1% of the cases in the sunitinib arm. Two patients in the sunitinib group died, but these deaths were determined to be unrelated to drug treatment.
Grade 3 and grade 4 palmar-plantar erythrodysesthesia was reported from treatment with sunitinib at rates higher than were seen in the ASSURE and PROTECT trials, and curiously, there was 1 reported instance of increased thyroid function.1,3
Although the original study’s proposed timeframe was supposed to be 1 year of treatment with sunitinib, only 56% of patients completed the full treatment period. Mean duration of treatment for both study arms fell short of 1 year: it was only 9.5 months for sunitinib and 10.3 months for placebo. Drug therapy was continued until disease relapse, occurrence of secondary malignancy, significant toxicity, death, or withdrawal of consent.
Even though the difference in the mean HRQoL scores across the sunitinib and placebo groups was considered statistically significant in favor of placebo (P = .0001), the investigators still concluded there was “no clinically meaningful deterioration” in the quality of life scores from patients given sunitinib.
In sum, patients administered sunitinib as an adjunctive therapy reported increased symptoms and reduced HRQoL scores. Despite this observation, the investigators still concluded that AEs were “predictable, manageable, and reversible” and that “adjuvant therapy was not associated with clinically meaningful deterioration in most quality of life measures.”2
While sunitinib was approved by the US Food and Drug Administration in November 2017 as an adjuvant treatment in adult patients at high risk of recurrent renal cell carcinoma following kidney removal, in February 2018, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended against the label expansion of sunitinib for this indication.
According to Pfizer financial documents, the company had requested a re-examination of the data — but it also added that by June 2018, it had completed discussions with the EMA and had “decided to withdraw [the] application based on the CHMP’s view that the data provided do not allow the CHMP to conclude on a positive benefit-risk balance for the proposed indication.”4
In fact, according to Bishal Gyawali, MD, PhD, a physician from Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, who was not involved in the current study, the FDA should never have approved sunitinib for this indication in the first place.
“Unlike metastatic setting where [progression-free survival] is sometimes considered acceptable, [overall survival] is a must for adjuvant treatments because these are patients who have undergone surgery to remove their tumor and we are asking these patients who are now tumor-free — and some of whom may not relapse — to take a drug as toxic as sunitinib for 1 year,” Dr Gyawali said to Cancer Therapy Advisor via email. “Improvement in survival is the minimum the drug should offer to patients. However, this drug consistently failed to improve survival in [the] S-TRAC and ASSURE trials. Furthermore, even the purported DFS benefit is controversial because DFS didn’t improve in ASSURE, only in S-TRAC, and the meta-analysis of these 2 trials showed that adjuvant sunitinib did not improve even DFS while significantly increasing toxicities.”
Dr Gyawali continued, “[T]his new QoL paper should be the final nail in the coffin for this debate … now we have a drug for adjuvant setting we want to give for 1 year to cancer patients who don’t have [a] tumor in their body and this drug doesn’t improve survival, doesn’t improve DFS (based on pooled data), and also makes patients feel worse … the EMA is very correct in its recommendation and Pfizer’s withdrawal strikes me as the obvious conclusion.”
Disclosure: The Annals of Oncology study was funded by Pfizer. For a full list of author disclosures, please see the original study.
- Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375;2246-2254.
- Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387:2008-2016.
- Staehler M, Motzer RJ, George DJ, et al. Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial [published online August 23, 2018]. Ann Oncol. doi: 10.1093/annonc/mdy329
- Pfizer Inc. Form 10-Q. https://www.sec.gov/Archives/edgar/data/78003/000007800318000070/pfe-07012018x10q.htm. Updated July 1, 2018. Accessed September 5, 2018.