First-line panitumumab plus capecitabine for the treatment of older patients with wild-type RAS metastatic colorectal cancer. The phase II, PANEL study

Highlights

• Panitumumab has a low rate of immunogenicity compared with other antibodies against EGFR because of its fully human nature.

• The combination of panitumumab and capecitabine was suggested to be effective in older patients with WT RAS mCRC.

• The good tolerability and safety profile of the combination were in line to previous studies in older patients.

• Panitumumab with capecitabine may provide an alternative to other anti-EGFR regimens in older patients with WT RAS mCRC.

Abstract

Background

Despite the high morbidity and mortality of metastatic colorectal cancer (mCRC) in older patients, they have been underrepresented in clinical trials and their optimal treatment is yet to be determined. This open-label phase II study evaluated the benefits of panitumumab and capecitabine as a first-line chemotherapy regimen in older patients with wild-type [WT] RAS mCRC.

Patients and Methods

Patients (≥70 years; ECOG≤2) received 3-week cycles of panitumumab (9 mg/kg on day 1) plus capecitabine (850 mg/m² twice daily on days 1–14) until disease progression or unacceptable toxicity. Response was evaluated every 9 weeks according to RECIST_1.1. Outcome measures were: objective response rate (ORR), duration of response (DoR), time to response (TTR), progression (TTP) and treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety.

Results

Twenty-seven patients (11 women; median age: 78 years; ECOG: 0 [26%], 1 [67%], 2 [7%]) were evaluated. Median follow-up was 17.7 months. Confirmed ORR (95%CI) was 44.4% (25.7–63.2), with 25.9% of patients achieving at least stable disease. Median (95%CI) DoR was 8.7 (5.5–10.4) months, and median TTR was 2.2 (1.9–2.8) months. Median TTP was 9.6 (4.8–11.5) months, with a median TTF of 5.2 (2.8–7.2) months. The median PFS was 7.5 (4.4–10.4) months, and the median OS was 23.7 (7.4–27.5) months. Seventeen (63%) patients reported panitumumab and/or capecitabine-related adverse events grade 3–4, with skin toxicity (18.5%) being the most common. Two (7.4%) deaths were treatment-related.

Conclusion

This study suggests that panitumumab plus capecitabine is a safe and effective regimen in older patients with WT RAS mCRC.

Introduction

Colorectal cancer (CRC) is one of the most common malignancies in Western countries and remains the second and third-most common cancer in women and men, respectively [1]. Patients with CRC are usually older, with 67% of patients aged 65 years or older at the time of diagnosis. The number of older population diagnosed with this malignancy is expected to increase markedly in the near future [2,3].

Generally, cutting-edge research on new treatment strategies does not include older populations; in fact, many clinical trials exclude older patients. If included, this age group is often underrepresented, precluding meaningful conclusions on safety and efficacy [4]. Therefore, healthcare professionals face an information gap when treating this population with an often poor functional status, important comorbidities and fragility.

In the treatment of metastatic CRC (mCRC), the development of new biological molecules targeting the epidermal growth factor receptor (EGFR), such as panitumumab and cetuximab, has been a key factor in major advances in mCRC treatment [5]. In particular, these two agents have been shown to significantly improve patient outcomes, either used alone or in combination with chemotherapy [6].

In 2012, the Spanish Digestive Tumour Treatment Group (TTD) investigated the effect of the combination of capecitabine and anti-EGFR cetuximab in older patients. In our study, patients receiving cetuximab (loading dose of 400 mg/m² and 250 mg/m² weekly) plus capecitabine (1000 mg/m²/12h, days 1–14, every 3 weeks [Q3W]) presented a response rate of 48.3% (95% CI: 29.4–67.5%) with a median progression free survival (PFS) of 8.6 months and a median overall survival (OS) of 19 months, respectively, in patients with wild-type (WT) KRAS [7]. Panitumumab, a fully human anti-EGFR mAb, has been shown to be active in monotherapy and in combination with chemotherapy in patients with WT RAS mCRC. Panitumumab does not show the immunogenic activity of cetuximab, despite having the same mode of action and spectrum of activity [8]. Furthermore, due to its pharmacokinetic profile, panitumumab can be administered Q2W or Q3W, allowing to synchronize with chemotherapy schemes administered in the same way.

In older patients, capecitabine, a prodrug of fluorouracil, has shown to be effective and well tolerated as first-line monotherapy and has become a consolidated alternative to the 5-fluorouracil/leucovorin combination [9].

Therefore, the addition of panitumumab to capecitabine is expected to improve its efficacy while maintaining a favourable toxicity profile and, thanks to its Q3W administration schedule, to become an attractive option for older patients with WT RAS mCRC. In this phase II study we aimed to investigate the response rate in older patients with WT RAS mCRC treated with panitumumab and capecitabine as a first-line chemotherapy regimen.