First-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS-BRAF wild-type metastatic colorectal cancer elderly patients: The PANDA study.

Abstract

4002 Background: Data on first-line treatment efficacy in elderly patients are limited. Many analyses adopt a questionable cut-off of 65 years and specific evidence with anti-EGFRs is low. FOLFOX-panitumumab (pan) is an option for RAS wild-type (wt) untreated mCRC patients. Guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, but no randomized studies have ever explored the role of the combination with an anti-EGFR. Methods: This is a prospective, open-label, multicenter phase II randomized trial. Unresectable and previously untreated RAS- BRAF wt mCRC patients aged ≥70 were randomized to receive FOLFOX-pan (arm A), or 5FU/LV-pan (arm B) for up to 12 cycles followed by pan maintenance until PD. The primary EP was PFS in both arms. Stratification criteria were age (≤75 vs > 75 years), ECOG PS (0–1 vs 2) and geriatric assessment with G8 Score (≤14 vs > 14). In each treatment arm, the null hypothesis for median PFS was set at ≤6 months. Assuming an expected median PFS time ≥9.5 months with both experimental regimens, a sample size of 90 patients in each arm granted to the study a power of 90%, with a type I error rate equal to 5% (1-sided Brookmeyer-Crowley test) for rejecting the null hypothesis. No formal comparison between the two arms was planned. Results: From Jul 2016 to Apr 2019 a total of 394 patients were screened, 211 were deemed eligible for inclusion and 185 were randomized (92 arm A and 93 arm B). Main pts’ characteristics were (arm A/B): males 66%/61%; median age 77/77y; PS≥1 49%/55%; right colon 23%/21%; G8 > 14 31%/30%. At a median follow up of 20.5 mos, 135 (arm A/B: 64/71) PD events were collected. Median PFS was 9.6 (95% CI 8.8-10.9) in arm A with FOLFOX-pan and 9.1 (95% CI 7.7-9.9) in arm B with 5FU/LV-pan. Response rates were (arm A/B): 65%/57%. Grade 3-4 toxicities were (arm A/B): neutropenia 9.8%/1.1%; diarrhea 16.3%/1.1%; stomatitis 9.8%/4.4%; neurotoxicity 3.3%/0%; fatigue 6.5%/4.4%; skin rash 25%/24.2%, hypomagnesemia 3.3%/7.7%. Conclusions: Large prospective randomized studies in molecularly selected elderly mCRC are feasible with multicenter collaborative efforts. Primary EP was met in both treatment arms. 5FU/LV plus panitumumab for up to 12 cycles followed by panitumumab maintenance until PD might be a reasonable option in elderly mCRC patients with RAS/BRAF wt tumors deserving further investigations in phase III trials. Clinical trial information: NCT02904031 .

First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis

“…In addition, a retrospective analysis of observational data from the Hellenic Oncology Research Group's database suggested that panitumumab was effective (median PFS 9.4 months; median OS 23.0 months) and well-tolerated in patients with mCRC aged ≥ 65 years ( n = 110) [ 27 ]. This finding was supported by the results of the prospective phase II PANDA trial [ 28 ], in which 185 patients aged ≥ 70 years received panitumumab in combination with folinic acid/5-fluorouracil, with or without oxaliplatin. The median PFS was 9.6 months among oxaliplatin recipients versus 9.1 months for those randomised to folinic acid/5-fluorouracil only.…”

Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study

“…Considering that doublet chemotherapy increased the toxicity burden, monochemotherapy plus anti-EGFRs was suggested as a reasonable first-line option in elderly RAS wild-type mCRC patients. 21 Nevertheless, it should be noted that combination chemotherapy achieves a higher response rate and a deeper tumor shrinkage, thus representing the optimal choice in fit elderly patients with high tumor burden and disease-related symptoms or if the treatment goal is downsizing to reach secondary resection. Finally, focusing on the selected subgroup of patients aged 70-75 years and fit enough for an intensified and highly active regimen, the pooled analysis of the TRIBE and TRIBE2 trials showed that the FOLFOXIRI triplet plus bevacizumab induced a significantly higher burden of chemotherapy-related toxicity, potentially severely impairing the QoL of this elderly population.…”

Chemotherapy and Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer

“…PANDA study is a randomized phase II trial comparing FOLFOX–panitumumab vs. 5-FU–LV–panitumumab in untreated RAS-BRAF wild-type patients aged ≥70 years. Median PFS was similar in both arms (9.6 and 9.1 months, respectively), although grade 3–4 toxicity was more frequent in the FOLFOX–panitumumab arm, particularly diarrhea and neutropenia [ 79 ]. Analysis of subgroups of elderly patients treated in a trial that compared panitumumab with best supportive care revealed no significant difference for toxicity or efficacy compared with younger patients [ 80 ].…”

“…The ESMO/MBCS 1.1. scale could not be applied to the anti-EGFR phase II clinical trials, because of the early closure secondary to lack of recruitment in the SAKK 41/10 trial [ 77 ], and because a formal comparison between the two arms was not planned in the PANDA study [ 79 ].…”

“…Additionally, the initial chemotherapy doses were arbitrarily decreased in some clinical trials [ 51 , 52 ], which potentially could have an impact on the efficacy and survival: a dose adjustment in a vulnerable patient can be adequate, but the same adjustment in a fit patient could imply an undertreatment. Other aspect to take into account in the clinical trials design is that the primary objectives are often overly conformist, limited to demonstrating an increase in PFS [ 51 , 52 , 57 , 59 , 79 ]. However, this benefit probably has no value without a parallel significant OS increase and/or quality of life improvement.…”