Life under the CABOSUN: Cabozantinib improves quality‐adjusted survival in comparison with sunitinib

In the article by Chen et al that accompanies this editorial, a quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of the Cabozantinib Versus Sunitinib as Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial (CABOSUN) lends insight into the quality-of-life advantage from the use of cabozantinib in comparison with the previous standard of care, sunitinib. Treatment for metastatic clear cell renal cell carcinoma (mRCC) was revolutionized by the use of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors with the discovery of von Hippel-Lindau (VHL) inactivation and subsequently hypoxia-inducible factor 1α (HIF-1α) and resultant VEGF overexpression. This established the use of VEGF inhibitors as the mainstay of treatment for several years until the more recent transition to the use of immunotherapy as monotherapy or in combination with VEGF inhibitors with the discovery of the beneficial effects of immunotherapy as a treatment option. Since the initial US Food and Drug Administration approval of sunitinib in 2006, it has become the default standard of care for first-line systemic treatment of mRCC and has, therefore, been used as the de facto comparator arm for most contemporary first-line therapy trials, including the Alliance-led CABOSUN trial. In brief, CABOSUN was a randomized phase 2 trial conducted by the Alliance for Clinical Trials in Oncology (A031203), which enrolled a total of 157 patients who were randomized to either cabozantinib (n = 79) or sunitinib (n = 78) with intermediateor poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. This trial demonstrated a median progression-free survival (PFS) of 8.6 months (95% confidence interval [CI], 6.8-14.0 months) with cabozantinib and a median PFS of 5.3 months with sunitinib (95% CI, 3.0-8.2 months) with a hazard ratio of 0.48 (95% CI, 0.31-0.74) and ultimately led to US Food and Drug Administration approval of cabozantinib as a first-line treatment for mRCC for all risk groups according to the IMDC criteria. Although cabozantinib offers a modest PFS advantage, it also comes with potential toxicities that are commonly seen with the use of VEGF inhibitors and may affect patients on a daily basis. Therefore, health-related quality-of-life measures along with Q-TWiST measures have been used to quantify these risks and improvements in quality of life. Q-TWiST has been used for more than 2 decades to assess the balance of the clinical benefits (prolongation of PFS) and toxicities of oncology treatments. This analysis has evolved over time from simply grading toxicity to measuring patients’ perceptions of symptoms of the disease, to quantifying side effects of treatment, to further integrating qualityand quantity-of-life measurements for adjuvant chemotherapy, and ultimately to comparing new treatments with the known standard of care. Historically, the 3-step method necessary to apply a Q-TWiST assessment includes defining the key primary quality of life–oriented endpoints, segregating the overall survival (OS) time into partitions, and comparing the treatment arms with respect to their quality-adjusted parameters of survival and toxicity. Analysis using Q-TWiST has also been employed historically to measure quantifying differences in quality-of-life measures. Although there is no established consensus on what constitutes a clinically meaningful difference, Revicki et al suggested that a composite difference of approximately 12% to 26% in PFS and a 5% to 10% difference in standard utility scores is clinically significant. On the other hand, a more focused RCC study showed various weighted utility values as a guide for future studies, including a utility value of 0.795 for stable disease, a demonstrable decrement utility value of 0.355 for progressive disease, and different utility grading for other toxicities such as 0.751 for grade 1 and 2 fatigue and 0.469 for grade 3 hand-foot syndrome. For the Q-TWIST analyses of the CABOSUN trial, Chen et al analyzed 3 parameters: 1) TWiST (or time without symptoms of disease or toxicity), which was defined as the time without disease progression and without any toxicity;