The present phase II study proposing FIr-B/FOx association in first line treatment of consecutive, unselected MCRC pts, reached the primary endpoint: ORR 82% in the ITT and 84% in the as-treated analysis. After a median follow-up of 21 months, median PFS was 12 months and 24% of pts were progression-free > 12 months; median OS was 28 months and 80% of pts (40 pts) were alive > 12 months.
The subsequent generations of randomized studies [8, 10, 11, 13, 14, 17, 18] showed increased activity and efficacy starting from ORR ≤ 20%, PFS 5 months and OS ≤ 14 months of 5-FU alone. Doublets consisting of CPT-11, or OHP, or BEV associated to 5-FU or Capecitabine gained ORR 20.0-47.0%, PFS 5.9-9.0 months and OS 15.1-21.5 months, without demonstrating differences between 5-FU/BEV associations compared to 5-FU or Capecitabine with CPT-11 or OHP. Triplets consisting of chemotherapeutic drugs or doublets plus BEV obtained ORR 39.0-66.0%, PFS 8.3-10.6 months and OS 20.3-26.1 months. In particular, the addition of a third drug, either BEV or OHP, equivalently increased the efficacy of doublet combination associating 5FU/CPT-11; 5-FU or Capecitabine and OHP plus BEV shows OS 20.4-26.1 months [13, 14]. Based on these data, a phase II study of four drug association, adding BEV to FOLFOXIRI, was recently proposed .
We previously showed that doublet and triplet chemotherapy using TFI/5-FU, without Leucovorin, according to the present schedule [19, 20], obtained equivalent efficacy to other reported schedules (ORR 40% and 66.7%, PFS 10 and 12 months, OS 21 and 20 months, respectively) and demonstrated a good tolerability profile [19, 20, 28]. In this scenario, Poker combination, adding BEV to FIr-FOx association, in first line treatment of MCRC, increased activity compared to triplet associations and it also increased efficacy; the 48% young elderly pts enrolled showed equivalent activity and efficacy.
Randomized studies of doublets (5-FU plus CPT-11 or OHP) adding Cetuximab (an EGFR-inhibitor) in EGFR-overexpressing pts, showed equivalent efficacy to other triplet combinations [29, 30]; in these studies, k-ras wild-type status was reported as a statistically relevant predictive biomarker of higher activity and efficacy. Preliminary data of a phase III trial may also confirm this with Panitumumab plus FOLFOX4 . The effectiveness of BEV-containing treatments was maintained in k-ras wild-type as it was in k-ras mutated pts .
Liver metastasectomies were performed in 26% of MCRC pts and 39% of pts with liver metastases. Moreover, 54% of pts with liver-only metastases and 50% of pts with initially unresectable liver metastases underwent surgical resection. Liver metastasectomies were reported in 8-11% of pts treated with triplet chemotherapy (36% in liver-only pts) [17, 18] and in 7.6% of pts in BEV-containing associations (15.2% in liver-only pts) ; in pts with potentially curable liver metastases, they were 92.8% . In Cetuximab-containing associations [29, 30], metastasectomies were performed in 7% and 4.7% of overall pts [29, 30]; 9.8% of KRAS wt pts . More, using neoadjuvant Cetuximab with either FOLFOX6 or FOLFIRI for unresectable colorectal liver metastases, metastasectomies were performed in 38% and 30% of pts, respectively . Our data show that more active first line treatment of MCRC , such as Poker combination, contribute to increase efficacy also by raising surgical resection of liver metastases.
Median rDIs per cycle and per patient were > 80% for each drug; in young elderly pts, only the rDI of CPT-11 was lower than 80% (76%; 61 mg/m2/w). Cumulative G3-4 toxicities were prevalently represented by diarrhea (28%), stomatitis/mucositis (6%), asthenia (6%), hypertension (2%), hypertransaminasemy (4%), neutropenia (10%). Cumulative G3-4 toxicities reported with the schedule associating BEV to 5-FU/Leucovorin or IFL were represented by equivalent prevalence of, respectively: diarrhea 28.5% and 32.4%; hypertension 8.5% and 11%; thrombotic events 14.2% and 19.4% [8, 11]. Cumulative G3-4 toxicities reported with FOLFOXIRI schedules [17, 18] were prevalently represented by, respectively: diarrhea 20% and 27.7%, stomatitis/mucositis 5% and 5%, asthenia 6% and 5.6%, neutropenia 50% and 35%, febrile neutropenia 5% and 7%, neurotoxicity 2% and 5.8%. Thus, gastrointestinal toxicities were not quite different in patients treated with 5-FU and CPT-11 as doublet, or associated to BEV, or OHP, or BEV and OHP as in the present study. Preliminary safety data of the phase III trial evaluating BEV plus FOLFOXIRI versus BEV plus FOLFIRI, show cumulative G3-4 toxicities prevalently represented by diarrhea (18%), stomatitis/mucositis (8%), asthenia (4%), hypertension (2%), trombotic events (8%), neutropenia (53%), febrile neutropenia (6%); a treatment-related death was reported in 1 patient (gastrointestinal bleeding; 2%). Thus, FIr-B/FOx schedule determined only 10% G3-4 neutropenia, while FOLFOXIRI schedule, added or not to BEV [35, 17], prevalently induced it (53% and 50%, respectively) and also febrile neutropenia (6% and 5%, respectively).
Cumulative G3-4 toxicities in young-elderly pts were prevalently represented by diarrhea (25%), hypertransaminasemy (4%), neutropenia 12.5%, stomatitis/mucositis (12.5%), asthenia (12.5%). Souglakos et al reported a significantly higher incidence of G3-4 diarrhea in elderly versus non-elderly pts either in the FOLFIRI or in the FOLFOXIRI arm . In our study, DLT was observed in 44% of pts and in 46% of young-elderly pts, with no differences of cumulative G3-4 toxicities by pts and by cycles. The innovative clinical evaluation of LTS, consisting of at least the DLT associated or not to other G2 or limiting toxicities, was introduced to better evaluate, in the individual patient, the presence of DLT alone, LTS-ss, or the association of major toxicities in different sites, LTS-ms: overall, they were 20% and 24% respectively; among young-elderly pts, they were 8% and 37.5%, respectively. Most LTS-ms (2 double DLTs and 7 out of 10 DLT associated to other, at least G2, non-limiting toxicities) were observed in this subgroup. LTS-ms were mostly represented by diarrhea and/or stomatitis/mucositis associated to nausea, vomiting and/or asthenia.