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Tweaking Maintenance Options in Metastatic CRC

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Two maintenance strategies for metastatic colorectal cancer (CRC) reduced the risk of disease progression or death following first-line chemotherapy, a pair of randomized trials from Europe found.

In the German PANAMA study, adding panitumumab (Vectibix) to maintenance treatment with 5-fluorouracil (5-FU) plus leucovorin improved median progression-free survival (PFS) from 5.7 months to 8.8 months in patients with RAS wild-type disease (HR 0.72, 80% CI 0.60-0.85, P=0.014), reported Dominik Paul Modest, MD, of the University Hospital of Munich.

“The combination of 5-FU-leucovorin plus panitumumab should be regarded as a preferred option of maintenance therapy following FOLFOX/panitumumab in patients with RAS wild-type metastatic colorectal cancer,” Modest concluded.

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Meanwhile, median PFS in the FOCUS4-N trial extended from 1.9 months with active monitoring to 3.8 months with capecitabine maintenance among a group of patients without targetable tumor mutations (BRAF, PIK3CA, KRAS/p53), who responded or had stable disease following first-line chemotherapy (adjusted HR 0.38, 95% CI 0.28-0.51), according to Richard Adams, MD, MBBS, of Cardiff University and Velindre Cancer Centre in Wales.

“Capecitabine maintenance strategy is a reasonable option for a clinician to discuss with their patient at the end of their first-line induction chemotherapy — essentially doubles the time until they’ll need to return to full-dose induction standard anti-cancer therapy,” said Adams. “FOCUS4-N lays out choices between increased toxicities and progression-free survival, which help and inform that discussion.”

Findings from the two trials were presented during the virtual American Society of Clinical Oncology (ASCO) annual meeting.

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“Will these results change our practice? I do not think so,” said ASCO-invited discussant Wen Wee Ma, MBBS, of the Mayo Clinic in Rochester, Minnesota.

“I think maintenance therapy should be considered for patients who achieve control when undergoing induction chemotherapy,” he said. “I think this is especially so for those patients who only achieve stable disease as best response during induction.”

For responders to induction chemotherapy, Ma suggested that perhaps less is more, as these patients likely have a more favorable tumor biology, and maintenance in this group with capecitabine or 5-fluorouracil-leucovorin alone may be sufficient.

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“Where do we go from here?” he said. “If we are reading a history book on maintenance treatment in metastatic colorectal cancer, we’re likely at the last few pages. Unless there are new frontline therapeutics to be evaluated or promising predictive biomarkers, I think it is time to focus our precious resources onto other more urgent questions in the field.”

PANAMA

The phase II PANAMA trial included 377 metastatic CRC patients with RAS wild-type disease who had been treated with FOLFOX plus panitumumab and had responded or achieved stable disease. Patients were then randomized 1:1 to maintenance 5-FU-leucovorin alone or with panitumumab. PFS following maintenance therapy was the primary endpoint.

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The overall response rate (ORR) with maintenance therapy was significantly higher in the panitumumab arm, at 40.8% compared with 26% with 5-FU-leucovorin alone (OR 1.96, 95% CI 1.14-3.36, P=0.02), including complete responses in 7.2% versus 4.9%, respectively.

Exploratory PFS analyses showed that most subgroups either benefited from the addition of panitumumab or favored that arm, though no benefit was seen for patients requiring reduced doses.

Median overall survival (OS) reached 28.7 months in the study arm versus 25.7 months in the control arm (HR 0.84, 95% CI 0.60-1.18, P=0.32), though Modest cautioned that with only 54% of OS events being recorded it’s too early to draw firm conclusions.

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Use of re-induction chemotherapy (with FOLFOX/panitumumab) was less frequent in the investigational arm compared with the control arm (45 vs 75 patients). But interestingly, PFS and ORR following re-induction were both far superior in control-arm patients.

Median PFS following re-induction was 3.3 months in the panitumumab arm compared with 5.8 months in the 5-FU-leucovorin-alone arm (HR 2.62, 95% CI 1.71-4.02, P<0.001). ORRs with re-induction were 8.9% and 34.7%, respectively (OR 0.18, 95% CI 0.06-0.57, P=0.002).

“The low frequency and moderate efficacy of re-induction following maintenance with 5-FU-leucovorin plus panitumumab suggests that induction of a new treatment line rather than re-induction of the initial treatment regimen may be a more favorable option,” said Modest.

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Ma noted that “a simplistic calculation” of PFS for maintenance plus re-induction with the panitumumab approach suggested a total improvement of “just 2 weeks.”

“It is unclear if that is clinically meaningful enough to recommend that panitumumab should be included for all RAS wild-type patients during maintenance therapy,” he said.

Patients in PANAMA had a median age of 65-66 years, two-thirds were men, about 70% had undergone primary tumor resection, 80% had left-sided tumors and synchronous metastatic disease, and 43-49% had more than one organ involved. Patients were stratified by prior response, with roughly 80% having achieved complete or partial responses to their initial therapy and the remaining having stable disease as best response.

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Adverse events (AEs) occurred more frequently with panitumumab, the most common of which, versus 5-FU-leucovorin alone, included skin rash (26.4% vs 6.5%), stomatitis (21.6% vs 10.6%), paronychia (18.4% vs 4.9%), infections (16.8% vs 8.1%), hypomagnesemia (16.8% vs 0.8%), fatigue (16% vs 11.4%), and skin fissures (14.4% vs 3.3%).

Common grade 3/4 AEs with panitumumab included skin rash (7.2%), hypomagnesemia (6.4%), paronychia (4.8%), infections (4%), and skin fissures (2.4%).

FOCUS4-N

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From 2014 to 2020, the trial randomized 254 patients who had stable disease following 16 weeks of first-line chemotherapy, in an unblinded fashion, to either active monitoring or maintenance capecitabine (1,250 mg/m2 twice daily; 2 weeks on, then 1 week off). The primary endpoint was PFS, with OS, safety, and quality of life (QOL) among the secondary endpoints.

Certain characteristics — left-sided tumors, those with PIK3CA wild-type or no PTEN loss, and no prior EGFR inhibitor exposures — appeared to predict improved PFS with the maintenance approach.

The results compare favorably to the CAIRO3 study of maintenance capecitabine plus bevacizumab, said Adams. He noted that OS in both trials was not significantly improved with the maintenance approaches.

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OS in FOCUS4-N reached a median 15.2 months with active monitoring and 14.8 months with maintenance capecitabine (HR 0.93, 95% CI 0.69-1.27).

Toxicities were mostly grade 1/2, said Adams, but far more frequent with the maintenance approach, with higher rates of diarrhea, fatigue, nausea, and hand-foot syndrome. There were no significant QOL differences on the EQ-5D scale between the two arms.

  • Ian Ingram is Managing Editor at MedPage Today and helps cover oncology for the site.

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Disclosures

PANAMA was funded by Amgen and Arbeitsgemeinschaft Internistische Onkologie.

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Modest disclosed relationships with Amgen, Bristol Myers Squibb, Lilly, Merck KGaA, Merck Sharpe & Dohme, Onkowissen, Pfizer, Pierre Fabre, Roche, Sanofi, Servier, and Taiho Oncology.

FOCUS4-N was supported by Cancer Research UK.

Adams reported relationships with Amgen, AstraZeneca, Bayer, Merck Serono, Merck Sharp & Dohme, and Servier.

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Ma reported an institutional relationship with Wellstat Therapeutics, as well as institutional research funding from Actuate Therapeutics, Athenex, BioMed Valley Discoveries, Bristol Myers Squibb, Ipsen, Merrimack, and Sun Pharma.

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