In patients with <em>RAS </em>wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of progression-free survival compared with a combined regimen of panitumumab plus fluorouracil and leucovorin; however, the combination regimen showed a higher rate of treatment-related toxicities, according to results from the phase II noninferiority VALENTINO trial.<br />
In patients withRASwild-type metastatic colorectal cancer (mCRC), maintenance therapy with single-agent panitumumab (Vectibix) was inferior in terms of progression-free survival (PFS) compared with a combined regimen of panitumumab plus fluorouracil and leucovorin; however, the combination regimen showed a higher rate of treatment-related toxicities, according to results from the phase II noninferiority VALENTINO trial.
The 10-month PFS rate in the combined regimen group (arm A) was 59.9% (95% CI, 51.5%-69.8%) vs 49.0% (95% CI, 40.5%-59.4%) in the panitumumab-only group (arm B; HR, 1.51; 95% CI, 1.11-2.07;P= .01). During maintenance therapy, arm A had a higher incidence of grade ≥3 treatment-related adverse events (TRAEs; n = 36, 42.4% vs n = 16, 20.3%) and panitumumab-related adverse events (AEs; n = 27, 31.8% vs n = 13, 16.4%), compared with arm B.
“The rationale of a maintenance strategy with anti-EGFRs in absence of the fluoropyrimidine backbone is supported by the single-agent efficacy of such drugs in patients with molecularly selected mCRC…. The VALENTINO phase II study prospectively enrolled patients withRASwild-type mCRC and showed that maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxicity,” wrote the authors, led by Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, in the report published inJAMA Oncology. “This reinforces the clear PFS inferiority of single-agent panitumumab as maintenance treatment, so that a subsequent phase III trial would have an extremely low probability of meeting a primary endpoint of noninferiority.”
VALENTINO’s inclusion criteria included being treatment-naïve in the advanced setting, locally assessedRASwild-type status, unresectable disease, ECOG performance status of 0 or 1, and adequate bone marrow, liver, and renal function. The investigators excluded patients who had received adjuvant oxaliplatin-based chemotherapy and experienced a relapse during treatment or within 12 months of completion (or within 6 months in the case of adjuvant fluoropyrimidine monotherapy). Patients with relevant cardiovascular disease or other active malignancies were also excluded.
The trial’s protocol consisted of an 8-cycle induction regimen of panitumumab plus FOLFOX-4 for all participants (panitumumab, 6 mg/kg; oxaliplatin, 85 mg/m2on day 1; leucovorin calcium, 200 mg/m2; and fluorouracil, 400-mg/m2bolus followed by 600-mg/m2continuous 24-hour infusions at days 1 and 2, every 2 weeks). This was followed by a maintenance regimen of either panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab monotherapy (arm B). Patients in both treatment arms continued their maintenance regimens until progressive disease, consent withdrawal, unacceptable toxic effects, or death.
The investigators also recommended prophylactic doxycycline for all participants in the hopes of preventing skin rash. The protocol specified a dose of 100 mg/day for 5 consecutive days, given every other cycle starting at cycle 1, day 1.
PFS at 10 months was the primary endpoint of the trial. Secondary endpoints were safety, overall survival (OS), overall response rate (ORR), disease control rate (DCR), duration of response, and quality of life.
Among 229 patients with a median age of 64, a sizeable majority were male (66.8%) and patients’ demographic and disease characteristics were well-balanced. Progressive disease was the most common reason for discontinuation in 135 patients (59.7%), followed by resection for metastases in 32 (14.2%).
The median treatment duration was 7.4 months (range, 4.3-12.4) for the overall population. In arm A, the median treatment duration was 8.4 months (range, 4.7-14.0), while it was 7.0 months (range, 4.0-10.5) for arm B. A total of 169 survival events occurred in 169 patients, including 83 in arm A and 86 in arm B. Overall, there were 15 deaths without disease progression, 6 in arm A and 9 in arm B. Median follow-up was 18.0 months (range, 13.1-23.3). In arm A, the median PFS was 12.0 months (95% CI, 10.4-14.5), while the median PFS was 9.9 months (95% CI, 8.4-11.0) in arm B (log-rank testP= .006).
Overall, 74 patients died, including 40 in arm A and 34 in arm B. The OS rate at the median follow-up of 18 months was 66.4% (95% CI, 57.1%-77.2%) in arm A and 62.4% (95% CI, 52.3%-74.4%) in arm B (HR, 1.13; 95% CI, 0.71-1.81;P= .60). ORR and DCR showed no significant difference between arms. Among the 153 patients who achieved a response, the median duration of that response was 10.9 months (range, 5.8-21.0) in arm A and 9.0 months (range, 5.9-14.7) in arm B (P= .16).
About one-third of the total trial population (n = 52, 31.7%), experienced at least 1 grade ≥3 AE, including 36 (42.4%) in arm A and 16 (20.3%) in arm B. Diarrhea and stomatitis were the most common serious AEs in arm A (4 grade ≥3 diarrhea and 6 grade ≥3 stomatitis vs 1 each in arm B). Most patients had panitumumab-related toxic effects (mainly skin rash, paronychia, hypomagnesemia, and conjunctivitis), although the rates were higher in the combination arm. Serious neurotoxic AEs occurred in 7 patients (3.1%). Three patients died of sepsis during the induction phase.
The authors noted that the PFS benefit of adding fluorouracil/leucovorin to panitumumab in the maintenance setting did not differ according to main subgroups, including those with poorer prognosis and primary resistance to anti-EGFR agents, such as right-sided primary orBRAF-mutated tumors.
“The prevalence of right-sided tumors was only 17%, and that ofBRAF-mutated tumors was only 4%, therefore lower than expected in theRASwild-type population, showing an increased refinement of patients’ selection in the clinical practice,” the study authors wrote. “Even if the absence of a panitumumab-free arm did not allow us to perform predictive analyses, PFS in these 2 subgroups was particularly poor in arm B.”
Pietrantonio et al noted that quality-of-life data will be analyzed when a majority of patients have concluded treatment and will be presented in a separate publication.
Pietrantonio F, Morano F, Corallo S, et al. Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer A Phase 2 Randomized Clinical Trial [Published online July 3, 2019].JAMA Oncol. doi: 10.1001/jamaoncol.2019.1467.