Panitumumab Maintenance Combination Prolongs PFS in RAS Wild-Type mCRC

Dominik P. Modest, MD

In the phase 2 PANAMA trial (AIO KRK 0212 trial; NCT01991873), adding panitumumab (Vectibix) to 5-fluorouracil (5-FU) and leucovorin showed significant improvement in progression-free survival (PFS) as a maintenance treatment over 5-FU/leucovorin alone in patients with RAS wild-type metastatic colorectal cancer (CRC), according to data presented during the 2021 ASCO Annual Meeting.

The median PFS with the triplet maintenance regimen was 8.8 months (80% CI, 7.6-10.2) vs 5.7 months (80% CI, 5.6-6.0) with the doublet, leading to a 28% reduction in the risk of disease progression or death (HR, 0.72; 80% CI, 0.60-0.85; P = .014). Moreover, the exploratory PFS subgroup analysis suggested a relatively homogenous magnitude of benefit in all subgroups evaluated, according to lead study author Dominik P. Modest, MD, of Department of Medicine III, University Hospital, LMU Munich, Germany.

“Panitumumab is active as maintenance therapy in combination with 5-FU/leucovorin,” Modest said in a presentation on the data. “Therefore, the combination should be regarded as the preferred option of maintenance therapy following FOLFOX/panitumumab in patients with RAS wild-type metastatic CRC.”

Fluoropyrimidines had been established as a maintenance approach in this patient population after treatment with fluoropyrimidines and oxaliplatin, according to data from the OPTIMOX trial. For patients who received fluoropyrimidines plus oxaliplatin and bevacizumab (Avastin), the combination of a fluoropyrimidine and bevacizumab has become a preferred maintenance option.

In the context of frontline EGFR monoclonal antibodies, the optimal approach for maintenance continues to be an area of debate. Although it is hypothesized that these antibodies could prove to be active as a maintenance treatment, the backbone of 5-FU/leucovorin appears to be a necessary component. Optimal maintenance therapy following treatment with fluoropyrimidine, oxaliplatin, and EGFR-based induction therapy continues to be unclear.

In the phase 2 study, investigators enrolled patients with RAS wild-type metastatic CRC. Patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and acceptable organ function. Patients could not have been pretreated for metastatic disease, although 1 prior FOLFOX was permitted.

Study participants received FOLFOX plus panitumumab for 6 treatment cycles. Those who achieved disease control, meaning that they experienced partial or complete remission or stable disease, were then randomized 1:1 to receive either panitumumab plus 5-FU/leucovorin or 5-FU/leucovorin alone. Maintenance treatment was given until progressive disease or death. Notably, all patients for whom maintenance therapy failed were able to be retreated with FOLFOX/panitumumab.

The primary end point of the trial was PFS, which was defined as time from randomization to progression or death from any cause. “This was important. It was not inclusion, but randomization, or start of maintenance therapy to progression or death of any cause,” Modest noted. “The assumption of the trial was a relative improvement of the PFS by 25%, corresponding to a [hazard ratio] of 0.75. Power was 80%, with an alpha-error rate of 10%.”

Moreover, 218 events were needed for analysis of PFS, which led to the inclusion of up to 400 patients into the induction phase, and randomization of up to 270 patients into the maintenance therapy arms. Patients were stratified based on the following: objective responses vs stable disease following induction treatment, planned full vs reduced dosage of panitumumab, and prior adjuvant therapy with oxaliplatin (yes vs no).

A total of 387 patients were enrolled to the trial; of these, 377 received treatment with FOLFOX and panitumumab. A total of 112 patients dropped out; this was because of death (n = 6), disease progression (n = 19), secondary resections (n = 45), other medical reasons (n = 6), toxicities (n = 19), patient decision (n = 9), other reasons (n = 5), unknown reasons (n = 2), or randomization was stopped (n = 1).

A total of 265 patients underwent randomization; 133 were assigned to the panitumumab plus 5-FU/leucovorin arm, while 132 were assigned to the 5-FU/leucovorin alone arm. A total of 8 patients on the investigative arm and 9 patients on the control arm did not receive maintenance treatment. “The frequency of reinduction therapy was clearly higher in patients who received 5-FU/leucovorin alone as maintenance therapy,” Modest said. Seventy-five patients in the control arm vs 45 patients in the investigative arm were retreated.

Patient and disease characteristics were found to be generally well balanced between the arms. The median age of participants was 65.5 years, the majority (66.5%) were male, had an ECOG performance status of 0 (58.2%), and had previous resection of their primary tumor (70.9%).

“Of note, left-sided primary tumor location was clearly predominant, with about 80% [of patients] in both study arms having a left-side primary tumor,” Modest noted. “Also of interest, synchronous metastatic disease was reported in 80% vs 80.5% of patients in the investigative and control arms, respectively.”

Objective response rates (ORRs) of induction therapy were used as a stratification factor, according to Modest, and these were beyond 80%. In the investigative arm, the complete response/partial response rate was 80.8% vs 80.5% in the control arm. The stable disease rates were 19.2% and 19.5%, respectively. Moreover, the full dose of panitumumab was received in 79.2% and 84.6% of the treatment arms, respectively.

“That suggests that patients who underwent randomization were somehow selected for favorable efficacy and also favorable tolerability of the induction therapy,” Modest said.

Overall survival (OS) data for the trial are currently immature; however, Modest noted a small trend toward better outcomes with the addition of panitumumab to 5-FU/leucovorin. The median OS is 28.7 months (95% CI, 25.4-39.1) in the investigative arm vs 25.7 months (95% CI, 22.2-28.2) in the control arm (HR, 0.84; 95% CI, 0.60-1.18; P = .32).

Moreover, best objective responses were also evaluated. Results indicated that more patients in the panitumumab plus 5-FU/leucovorin arm achieved further responses vs 5-FU/leucovorin alone, at 40.8% vs 26.0%, respectively (odds ratio, 1.96; 95% CI, 1.14%-3.36%; P = .02).

Re-induction therapy was more frequently done in those who received 5-FU/leucovorin alone (n = 75) vs those who received the addition of panitumumab (n = 45). The PFS with re-induction was 3.3 months (95% CI, 2.0-4.0) in the investigative arm vs 5.8 months (95% CI, 4.5-8.0) in the control arm (HR, 2.62; 95% CI, 1.71-4.02; P <.001). The ORR rates in these arms were 8.9% and 34.7%, respectively (odds ratio [OR], 0.18; 95% CI, 0.06-0.57; P = .002). “Both efficacy end points were statistically significantly different and in favor of the 5-FU/leucovorin alone arm,” Modest noted.

Regarding safety, the investigative and control arms, respectively, experienced fatigue (any-grade, 16.0% vs 11.4%; grade 3/4: 0.8% vs 0.8%), pain (any-grade, 20.8% vs 22.8%; grade 3/4, 3.2% vs 4.9%), and infections (any-grade, 16.8% vs 8.1%; grade 3/4: 4.0% vs 0.8%).

“The highest frequency of grade 3 or 4 events was skin rash in the panitumumab arm, suggesting a very moderate toxicity profile,” Modest noted. Any-grade skin rash was experienced by 26.4% of patients in the investigative arm vs 6.5% of those in the control arm; this was grade 3 or 4 in 7.2% and 0% of patients, respectively.

“Maintenance therapy with 5-FU and leucovorin plus panitumumab was well tolerated,” Modest concluded. “The low frequency and moderate efficacy of re-induction following maintenance with 5-FU/leucovorin plus panitumumab suggest that the indication of a new treatment line rather than re-induction may be a more favorable option.”

_Reference

_{Modest DP, Karthaus M, Frühauf S, et al. Maintenance therapy with 5-fluoruracil/leucovorin (5FU/LV) plus panitumumab (pmab) or 5FU/LV alone in RAS wildtype (WT) metastatic colorectal cancer (mCRC): the PANAMA trial (AIO KRK 0212). J Clin Oncol. 2021;39(suppl 15):3505. doi:1200/JCO.2021.39.15_suppl.3503}