PANDA is a unique study specifically conducted in elderly patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) fit enough to potentially receive first-line treatment with an anti-EGFR agent added to infusional chemotherapy backbone. Notably, the 5-fluorouracil (5-FU) bolus was omitted in both study arms to improve chemotherapy tolerability without loss of efficacy. The study met its primary endpoint and demonstrated promising progression-free survival (PFS) in both arms of either modified FOLFOX (mFOLFOX) plus panitumumab or 5-FU plus leucovorin (LV) plus panitumumab, with a post-hoc evidence of similar PFS, overall survival (OS), and disease control rate.
As expected, several chemotherapy-related adverse events (AEs) were increased with mFOLFOX plus panitumumab. The study findings are published by Dr. Sara Lonardi of the Medical Oncology 1, Veneto Institute of Oncology IOV—IRCCS in Padova, Italy, and GONO Foundation investigators on 3 August 2023 in the JCO.
The authors wrote in the background that probability of developing CRC is <1% in the population younger than 70 years, but it reaches about 3% in people 70 years or older. In a meta-analysis of 20023 patients enrolled in 24 phase III studies and receiving first-line treatment for mCRC, the oldest group of patients had a 42% increased risk of death.
However, elderly patients with mCRC remain under-represented in clinical trials and the available data are mostly derived from retrospective or non-controlled studies and post-hoc analyses of randomised studies. Pivotal trials conducted in elderly populations showed a narrow therapeutic index of oxaliplatin- or irinotecan-based doublets, thus questioning the role of upfront combination chemotherapy in frail or very old patients. The guidelines suggest that fluoropyrimidine monotherapy or reduced doses of doublet regimens may be used in clinical practice after geriatric assessment.
Regarding the efficacy and safety of bevacizumab or anti-EGFR agents added to doublets, post-hoc analyses of randomised clinical trials did not show a major impact of older age in terms of PFS, OS, and grade 3-4 AEs. However, elderly patients eligible for those studies were a highly selected and small subgroup, with consequent lack of evidence on more frail and aged patients. To fill this gap, the phase III AVEX study established bevacizumab plus capecitabine as a valuable upfront option for patients with mCRC non-eligible for combination chemotherapy.
On the other hand, chemotherapy doublets plus anti-EGFR monoclonal antibodies are the preferred first-line treatment options for fit patients with RAS/BRAF wild-type, left-sided mCRC. However, the prospective studies conducted with panitumumab or cetuximab in elderly patients had a non-randomised design, small sample size, and absent or limited molecular selection. Moreover, no solid data about the efficacy of the combination of anti-EGFR agents with fluoropyrimidine monotherapy are available.
An open-label, randomised phase II non-comparative PANDA study was designed to explore the safety and efficacy of panitumumab added to infusional doublet chemotherapy schedule of mFOLFOX or monochemotherapy with 5-FU plus LV as initial treatment for patients aged 70 years and older with unresectable RAS/BRAF wild-type mCRC.
Patients were randomly assigned 1:1 to mFOLFOX plus panitumumab (arm A) or 5-FU plus LV plus panizumumab (arm B) for up to 12 cycles, followed by panitumumab maintenance. The primary endpoint was PFS. In each arm, assuming a null hypothesis of median PFS time ≤6 months and target PFS ≥9.65, 90 patients per arm were needed to achieve 90% power and 5% type I error by one-sided Brookmeyer-Crowley test.
Between July 2016 and April 2019, 91 patients were randomly assigned to arm A and 92 to arm B. At a median follow-up of 50.0 months, median PFS was 9.6 and 9.0 months for arm A and B (p < 0.001 in each arm). Overall response rate was 69% and 52%, whereas median OS was 23.5 and 22.0 months in arm A and B.
The overall rate of grade >2 chemotherapy-related AEs was 60% and 37%, respectively. Baseline G8 and Chemotherapy Risk Assessment Scale for High-Age Patients scores were prognostic, but they were not associated with efficacy and safety of the two arms.
The authors commented that the results of their study are not fully transferable to a population of more frail elderly patients where, in the absence of contraindications to antiangiogenic agents, capecitabine plus bevacizumab may still be a preferable treatment option, especially in right-sided primary tumours.
The study has limitations. It is characterised by a go/no go non-comparative design, where random assignment was needed to avoid imbalances in the baseline features but the statistical comparisons between the two arms were unplanned and conducted post-hoc. However, a phase III study would be hardly feasible in this patient population because of the clinical and molecular selection recommended for initial anti–EGFR-based treatment, the need to use a non-inferiority design to formally validate 5-FU plus LV plus panitumumab, thus requiring a very large sample size, and the risk of exposing frailer patients treated with mFOLFOX plus panitumumab to excessive toxicity burden with a potentially quite modest PFS and OS gain.
The authors concluded that both, mFOLFOX plus panitumumab or 5-FU plus LV plus panitumumab are reasonable options as initial treatment for elderly patients with RAS/BRAF wild-type mCRC, but 5-FU plus LV plus panitumumab is associated with a better safety profile. These data provide a better level of evidence to support the choices that physicians make in everyday clinical practice.
Findings were previously presented in part at ASCO 2020 Annual Meeting.
Amgen provided panitumumab in arm B and partially supported the study.
Reference
Lonardi S, Rasola C, Lobefaro R, et al. on behalf of GONO Foundation Investigators. Initial Panitumumab Plus Fluorouracil, Leucovorin, and Oxaliplatin or Plus Fluorouracil and Leucovorin in Elderly Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer: The PANDA Trial by GONO Foundation. JCO; Published online 3 August 2023. DOI: 10.1200/JCO.23.00506
