Although the optimal approach to maintenance is not definitive in patients with metastatic colorectal cancer who have undergone chemotherapy-based induction with anti–endothelial growth factor receptor (EGFR) agents, the phase II VALENTINO trial showed that anti-EGFR maintenance therapy with panitumumab (Vectibix) is feasible in this patient population and may be most effective when combined with fluorouracil/leucovorin (5-FU/LV).

For patients with metastatic colorectal cancer who achieve disease control after induction chemotherapy with or without bevacizumab (Avastin), de-escalating treatment intensity has become the emerging standard of care. However, there is scarce evidence of a disease control benefit and an impact on quality of life associated with de-escalating treatment intensity after anti–EGFR-based induction.

Filippo Pietrantonio, MD

These findings were originally presented at the 2018 ASCO Annual Meeting by Filippo Pietrantonio, MD, of the Department of Medical Oncology, University of Milan, and colleagues.¹ The study was later discussed at the Best of ASCO Chicago by Wells Messersmith, MD, Professor and Head, Division of Medical Oncology, University of Colorado, Denver, along with other top selected abstracts in gastrointestinal cancers.²

The VALENTINO study, conducted at 29 centers in Italy, was designed to evaluate whether single-agent panitumumab was noninferior to maintenance with 5-FU/LV plus panitumumab following induction with combination chemotherapy plus an EGFR inhibitor.

“So, you’ve treated someone with FOLFOX-4 (oxaliplatin, 5-FU, and LV) for about 4 months and [he has] started to get neuropathy; he starts to ask if he has to be on this regimen for the rest of his life or he can take a break,” Dr. Messersmith explained. “The question becomes what to use for maintenance.”

Panitumumab/5-FU/Leucovorin

Between July 2015 and October 2017, the trial enrolled 229 patients with previously untreated, unresectable, RAS wild-type metastatic colorectal cancer who were stratified according to prior adjuvant therapy and the number of metastatic sites. All patients underwent up to 8 cycles of induction therapy with FOLFOX-4 plus panitumumab at 6 mg/kg every 2 weeks and were then randomized to receive maintenance therapy with panitumumab and 5-FU/LV (arm A; n = 117) or panitumumab alone (arm B; n = 112) until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival at 10 months.

About two-thirds of patients were male, with a median age of 62 years. About half of patients (53%–58%) had a single metastatic site, the majority (62%–64%) had undergone primary tumor resection, and between 14% and 18% had received previous adjuvant treatment. The tumor location was primarily on the left side (80%–84%), and most patients (95%–97%) had BRAF wild-type metastatic colorectal cancer.

After a median follow-up of 13.8 months, the 10-month progression-free survival rate favored the 5-FU/LV plus panitumumab group: 62.8% vs 52.8% with panitumumab alone, with a median progression-free survival of 13 months and 10.2 months, respectively (P = .011).

“You can see that 5-FU, the old workhorse drug, seems to be important here. By not giving 5-FU with panitumumab, you had a worse outcome,” he observed. “You also got about 3 months of progression-free survival benefit. If we had a new drug that gave 3 months of benefit, it would likely be approved. That’s something to consider.”

Panitumumab Monotherapy: ‘Completely Inferior’?

The hazard ratio for progression-free survival was 1.55 for panitumumab monotherapy relative to 5-FU/LV plus panitumumab (P = .011), which meant the trial did not meet the criteria for panitumumab noninferiority, set at a threshold of a hazard ratio less than 1.515. “It’s actually touching against this upper boundary, so not only is it noninferior, it actually seems to be completely inferior,” he noted. “And there really was no subgroup where panitumumab alone was favored.”

Response rates were similar in the treatment groups: 65.8% and 67% with combination therapy and single-agent therapy, respectively. However, patients treated with the drug combination had a longer duration of response than did those treated with panitumumab alone (12.6 months vs 9.8 months).

The VALENTINO study showed that if you’re going to maintain a patient with an EGFR inhibitor, you should think about including 5-FU/LV as well.

— Wells Messersmith, MD

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“In terms of the duration of response, unlike immunotherapy or some of the other [drugs] we’re using, these curves don’t flatten very well until you get out to just a few patients,” he added. “And 5-FU, again, seems to play an important role in maintaining response.”

Toxicities were manageable in both study arms during the maintenance phase, but adverse events were worse in the combination group. Grade 3 or worse adverse events were mainly diarrhea (3.7% vs 1.4%), mucositis (6.2% vs 1.4%), hand-foot syndrome (2.5% vs 1.4%), neutropenia (2.5% vs 0%), and skin rash (22.2% vs 13.7%).

“In patients with RAS wild-type metastatic colorectal cancer, anti-EGFR therapy in the treatment-naive setting of left-sided colon cancers can be considered a targeted therapy option,” said Dr. Messersmith. “I think the VALENTINO study showed that if you’re going to maintain a patient with an EGFR inhibitor, you should think about including 5-FU/LV as well.” ■

DISCLOSURE: Dr. Messersmith has served as a consultant/advisor for Gilead Sciences, Purdue Pharma, and Tanabe Research Laboratories; and has received funding from Pfizer, Takeda, Aduro Biotech, Roche/Genentech, OncoMed, Immunomedics, and Alexo Therapeutics.

REFERENCES

1. Pietrantonio F, Morano F, Corallo S, et al: First-line FOLFOX plus panitumumab followed by 5-FU/LV plus panitumumab or single-agent panitumumab as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer: The VALENTINO study. 2018 ASCO Annual Meeting. Abstract 3505. Presented June 5, 2018.

2. Messersmith W: Gastrointestinal (colorectal) cancer. 2018 Best of ASCO Chicago. Presented August 11, 2018.