I love a good plenary session at ASCO, and this year’s plenary session was one of the best I have seen. Three of the four presentations were investigator-initiated randomised trials answering important clinical questions, and two presentations (the TAILORx and CARMENA trials discussed below) reflected the refreshing and welcome ‘less is more’ mantra of ASCO 2018.
- TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score.
The TAILORx trial investigated the benefit of adjuvant chemotherapy in women with hormone-receptor positive, node negative, HER2 negative breast cancer and an intermediate recurrence score of 11 to 25 by the Oncotype DX genomic test. Eligible patients (n=6711) were randomised to chemoendocrine therapy or endocrine therapy alone. The trial was designed to show the non-inferiority of endocrine therapy for the primary endpoint of 5-year invasive disease-free survival (iDFS; freedom from invasive disease recurrence, second primary cancer, or death) with a non-inferiority margin of HR 1.322. In the ITT population, endocrine therapy was non-inferior to chemoendocrine therapy for iDFS (HR 1.08; 95% CI, 0.94 to 1.24; P=0.26) with 9-year iDFS rates of 83.3% in endocrine therapy arm and 84.3% in the chemoendocrine therapy arm. Subgroup analyses suggested a benefit of chemoendocrine therapy in patients aged ≤50 years with a recurrence score of 15 to 25.
The results of this trial mean that many women with early breast cancer do not need adjuvant chemotherapy, so avoiding the acute and chronic toxicities of the treatment. The main barrier for the translation of the results to clinical practice in Australia is that Oncotype DX is not reimbursed and the private cost (~$4-5000) is prohibitive to most patients. This will hopefully change very soon.
- CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—Results of a phase III noninferiority trial.
Cytoreductive nephrectomy prior to systemic therapy is the current standard of care for patients with newly diagnosed metastatic renal cell carcinoma (mRCC). The CARMENA trial questioned the need for cytoreductive nephrectomy the era of targeted therapy. The CARMENA trial was an open label, phase III trial that aimed to randomise 576 patients with newly diagnosed mRCC to nephrectomy followed by sunitinib or to sunitinib alone. The trial was designed to show the non-inferiority of sunitinib alone for the primary endpoint of overall survival (OS) with a non-inferiority margin of HR 1.20. The trial was stopped early at 450 patients after 8 years due to slow accrual. In the ITT population, sunitinib alone was non-inferior to nephrectomy and sunitinib for OS (median OS 18.4 months v 13.9 months respectively; HR 0.89; 95% CI 0.71 to 1.10) in both intermediate- and poor-risk populations as per MSKCC Score.
There are some caveats to the translation of the results of CARMENA to modern clinical practice and the expanding repertoire of systemic therapies, but the results mean that some patients suitable for first-line sunitinib do not need prior nephrectomy. The results also highlight the need for the presentation and discussion of all newly diagnosed patients with mRCC at multidisciplinary meetings prior to any treatment for consensus on the best approach to their care.
- Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas.
The Unicancer GI PRODIGE 24/CCTG PA.6 trial investigated the role of adjuvant modified FOLFIRINOX (mFOLFIRINOX) versus gemcitabine in resected pancreatic cancer. mFOLFIRINOX has no 5-FU bolus; during the trial the starting irinotecan dose was also reduced from 180mg/m2 to 150mg/m2. The trial was designed to determine the superiority of mFOLFIRINOX over gemcitabine with a primary endpoint of disease free survival (DFS). 493 patients were enrolled from 77 French and Canadian centres. Patients in the mFOLFIRINOX arm compared with the gemcitabine arm had higher use of G-CSF (59.9% v 3.7%, p<0.001) but similar rates of neutropenia and febrile neutropenia, overall more toxicity especially diarrhoea (eg gr ¾ 18.6% v 3.7%), and lower overall dose intensity (66.4% v 79.0%, p=0.002). mFOLFIRINOX improved DFS (median DFS 21.6 v 12.8 months; HR 0.58; 95% CI 0.46-0.73, p<0.0001), OS (median OS 54.4 v 35 months; HR 0.64; 95% CI 0.48-0.86, p<0.003) and other secondary endpoints of metastasis free survival and specific survival.
This trial was very well-received and was notable for the big improvements in survival with mFOLFIRINOX, the good performance of the control arm, and the benefits coming from good old chemotherapy. Despite the current standard of care being combination capecitabine and gemcitabine as per the ESPAC-4 trial, the results should have an immediate impact on clinical practice in Australia with mFOLFIRINOX the preferred adjuvant regimen for suitable patients.