A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only

Abstract

Lessons Learned

• This regimen is a viable option for patients with liver-only metastatic colorectal cancer.

• Enrollment criteria for future studies should include testing for the newly identified KRAS mutations.

Background.

Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis.

Methods.

Patients received FOLFOXIRI (5-FU, 3,200 mg/m², 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m² i.v.; irinotecan, 125 mg/m²; oxaliplatin, 85 mg/m² i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate.

Results.

Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1–33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all had complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found.

Conclusion.

KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.

Discussion

It was estimated that in 2015 there would be approximately 132,700 new cases of colorectal cancer and 49,700 deaths due to this disease [1]. While surgical resection of metastases is sometimes curative, most patients with liver metastases are not considered resectable because of the number or location of the metastases. Advances in the first-line treatment of metastatic colorectal cancer (mCRC), with increased response rates, can convert some patients with initially unresectable liver metastases to resectable, allowing for potentially curative treatment.

In the phase II OLIVIA trial, patients with liver metastases from mCRC were randomized to bevacizumab plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) or FOLFOXIRI [2]. Bevacizumab/FOLFOXIRI was associated with higher rates of response (81% vs. 62%) and resection (61% vs. 49%), and prolonged median progression-free survival (mPFS) (18.6 months vs. 11.5 months), compared with bevacizumab/mFOLFOX6. In the phase III TRIBE trial, first-line therapy with FOLFOXIRI/bevacizumab was associated with improved mPFS (12.1 months vs. 9.7 months) and response rate (65% vs. 53%) compared with FOLFIRI/bevacizumab; however, there was no difference in R0 resection rate between treatments (15% vs. 12%) [3]. A subsequent analysis showed significant improvement in median overall survival (OS) with FOLFOXIRI/bevacizumab treatment (29.8 months vs. 25.8 months) [4]. Another phase II study evaluated panitumumab with FOLFOXIRI as first-line treatment with wild-type KRAS, HRAS, NRAS, and BRAF mCRC [5]. Thirty-three patients (89%) achieved objective response. Sixteen patients (43%) underwent resection of metastatic sites, with R0 resection performed in 13 patients (35%).

Based on the potential for improved response rates, we conducted a phase II study of panitumumab plus FOLFOXIRI as first-line treatment for patients with wild-type KRAS mCRC with liver-only metastases. Patients were eligible regardless of whether they were considered surgical candidates at baseline. After the protocol was initiated, new findings were published indicating that RAS mutations outside of KRAS exon 2 are also associated with inferior survival with combination panitumumab and oxaliplatin-based therapy [6]. Enrollment was halted while patients in the study underwent expanded KRAS/NRAS analysis. Eight of the 15 patients consented to expanded analysis, with no additional mutations identified. Of the 12 patients evaluable for efficacy, 75% achieved a partial response (PR) (Table 1). Ten patients underwent surgery; all had complete resections that showed pathologic PR. No significant safety signals were seen; the most common treatment-related adverse events (all grades) were rash (80%), diarrhea (60%), fatigue (53%), and nausea (53%). Despite early closure of the study, this regimen is a viable option for patients with liver-only mCRC.

Table 1.

Summary of clinical activities

Trial Information

Disease

Colorectal cancer

Stage of disease / treatment

Metastatic / Advanced

Prior Therapy

None

Type of study - 1

Phase II

Type of study - 2

Single Arm

Primary Endpoint

Overall Response Rate

Secondary Endpoints

Rate of R0 resection

Progression-Free Survival

Acute Toxicity Produced by the Regimen

Additional Details of Endpoints or Study Design

Planned enrollment was originally 49 patients.

Investigator's Analysis

Active and should be pursued further

Drug Information

Drug 1

Generic/Working name

Panitumumab

Trade name

Vectibix

Company name

Amgen

Drug type

Antibody

Drug class

Epidermal growth factor receptor

Dose

6 mg/kg

Route

IV

Schedule of Administration

Day 1 of each 14-day cycle with FOLFOXIRI

5-FU 3,200 mg/m², 48-hour continuous IV infusion

Leucovorin 200 mg/m² IV

Irinotecan 125 mg/m²

Oxaliplatin 85 mg/m² IV

Patient Characteristics

Number of patients, male

13

Number of patients, female

2

Stage

IV

Age

Median (range): 55 (39–70)

Number of prior systemic therapies

Median (range): 0

Performance Status: ECOG

0 — 12

1 — 3

2 — 0

3 — 0

Unknown — 0

Other

Baseline surgical candidate – yes: 10 (67%)

Baseline surgical candidate – no: 5 (33%)

Cancer Types or Histologic Subtypes

Adenocarinoma, 15

Primary Assessment Method

Control Arm: Total Patient Population

Number of patients enrolled

15

Number of patients evaluable for toxicity

15

Number of patients evaluated for efficacy

15

Response assessment CR

n = 0 (0%)

Response assessment PR

n = 9 (60%)

Response assessment SD

n = 3 (20%)

Response assessment PD

n = 0 (0%)

Response assessment OTHER

n = 3 (20%)

(Median) duration assessment PFS

13.3060 months, CI: 95%

Adverse Events

Assessment, Analysis, and Discussion

Completion

Study terminated before completion

Pharmacokinetics / Pharmacodynamics

Not Collected

Investigator's Assessment

Active and should be pursued further

It was estimated that in 2015 there would be approximately 132,700 new cases of colorectal cancer and 49,700 deaths due to this disease [1]. While surgical resection of metastases is sometimes curative, most patients with liver metastases are not considered resectable because of the number or location of the metastases. Advances in the first-line treatment of metastatic colorectal cancer (mCRC), with increased response rates, can convert some patients with initially unresectable liver metastases to resectable, allowing for potentially curative treatment.

In the phase II OLIVIA trial, patients with liver metastases from mCRC were randomized to bevacizumab plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) or FOLFOXIRI [2]. Bevacizumab/FOLFOXIRI was associated with higher rates of response (81% vs. 62%) and resection (61% vs. 49%), and prolonged median progression-free survival (mPFS) (18.6 months vs. 11.5 months), compared with bevacizumab/mFOLFOX6. In the phase III TRIBE trial, first-line therapy with FOLFOXIRI/bevacizumab was associated with improved mPFS (12.1 months vs. 9.7 months) and response rate (65% vs. 53%) compared with FOLFIRI/bevacizumab; however, there was no difference in R0 resection rate between treatments (15% vs. 12%) [3]. A subsequent analysis showed significant improvement in median overall survival (OS) with FOLFOXIRI/bevacizumab treatment (29.8 months vs. 25.8 months) [4]. Another phase II study evaluated panitumumab with FOLFOXIRI as first-line treatment with wild-type KRAS, HRAS, NRAS, and BRAF mCRC [5]. Thirty-three patients (89%) achieved objective response. Sixteen patients (43%) underwent resection of metastatic sites, with R0 resection performed in 13 patients (35%).

Based on the potential for improved response rates, we conducted a phase II study of panitumumab plus FOLFOXIRI as first-line treatment for patients with wild-type KRAS mCRC with liver-only metastases. Patients were eligible regardless of whether they were considered surgical candidates at baseline. After the protocol was initiated, new findings were published indicating that RAS mutations outside of KRAS exon 2 are also associated with inferior survival with combination panitumumab and oxaliplatin-based therapy [6]. Enrollment was halted while patients in the study underwent expanded KRAS/NRAS analysis. Figures 1 and 2 present PFS and OS data from our study. Eight of the 15 patients consented to expanded analysis, with no additional mutations identified. Of the 12 patients evaluable for efficacy, 75% achieved a partial response (PR) (Table 1). Ten patients underwent surgery; all had complete resections that showed pathologic PR. No significant safety signals were seen; the most common treatment-related adverse events (all grades) were rash (80%), diarrhea (60%), fatigue (53%), and nausea (53%) (Table 2). Despite early closure of the study, this regimen is a viable option for patients with liver-only mCRC.

Figure 1.

Progression-free survival (n = 15).

Abbreviations: CI, confidence interval; PFS, progression-free survival.

Figure 2.

Overall survival (n = 15).

Abbreviations: CI, confidence interval; NR, not reached; OS, overall survival.

Table 2.

Treatment-related adverse events (n = 15 patients)

Disclosures

Ahmed Zakari: Celgene, Amgen (C/A); Ralph Boccia: Amgen (H); David Waterhouse: Bristol-Myers Squibb (C/A), Bristol-Myers Squibb, Lilly, Celgene, Genetech/Roche (H); Anthony Meluch: Astellas, Janssen (H). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board