by Dr. C.H. Weaver M.D. updated 4/2019
The addition of the targeted therapy Vectibix® (panitumumab) to chemotherapy improves progression-free survival in patients with newly diagnosed or previously treated metastatic colorectal cancer. The benefit only applies to the subset of patients whose cancer does not contain a mutation in the KRAS gene.
Vectibix is a precision cancer medicine that inhibits cancer cell growth and survival by targeting a protein known as the epidermal growth factor receptor (EGFR). Precision Cancer Medicine.is now considered one of the pillars of cancer therapy, joining the three longstanding pillars or surgery, radiation therapy and chemotherapy. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Vectibix is the first fully human monoclonal anti-EGFR antibody approved by the FDA for the treatment of metastatic colon cancer with wild type RAS. An estimated 40–50% of metastatic colorectal cancers contain a gene known as KRAS. Vectibix specifically benefits patients whose cancers are EGFR positive and do not contain the KRAS mutation. This is refereed to as wild-type RAS.
What is KRAS ?
Vectibix appears to benefit only those patients whose cancers do not contain a mutation in a gene known as KRAS. KRAS mutations occur in an estimated 40-50% of metastatic colorectal cancers and can be identified by testing a sample of tumor tissue.(2,3,4)
To assess KRAS mutations and response to Vectibix, researchers evaluated information from a Phase III clinical trial. The study assigned patients with previously-treated metastatic colorectal cancer to treatment with either Vectibix plus best supportive care (care to manage symptoms) or best supportive care alone.
- Roughly 60% of patients had cancers that contained non-mutated (normal) KRAS.
- Among the patients with non-mutated KRAS, Vectibix significantly improved progression-free survival. Among patients with mutated KRAS, Vectibix did not influence survival.
The researchers conclude that Vectibix appears to be effective only among patients with cancers that lack KRAS mutations. Assessment of KRAS status may help identify those patients who are most likely to respond to Vectibix.
Since research has indicated that agents targeted against the EGFR tend to be beneficial only among patients without a mutation in the KRAS gene. This appears to be a class effect, rendering patients with mutations in the KRAS virtually unresponsive to these agents.
Therefore, the NCCN has recommended that all patients with colorectal cancer undergo pre-treatment testing for the status of the KRAS gene so that patients with mutations can be spared from unnecessary therapy, time and expense.(5)
What do the studies show?
Phase III clinical trials have evaluated Vectibix in the first-line (initial) treatment and the second-line treatment of metastatic colorectal cancer.
First Line Vectibix Treatment of Advanced CRC
The initial study that evaluated Vectibix in newly diagnosed, metastatic colorectal cancer was known was PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy.(6) The study enrolled 1,183 patients. who were assigned to receive treatment with FOLFOX-4 chemotherapy alone or FOLFOX-4 plus Vectibix.
- Among patients without KRAS mutations, the addition of Vectibix delayed cancer progression. Progression-free survival was 9.6 months among patients treated with chemotherapy plus Vectibix compared with 8.0 months among patients treated with chemotherapy alone. Overall survival was 23.9 months among patients treated with chemotherapy plus Vectibix versus 19.7 months among patients treated with chemotherapy alone.
- Among patients with KRAS mutations, the addition of Vectibix worsened outcomes. Progression-free survival was 7.3 months among patients treated with chemotherapy plus Vectibix compared with 8.8 months among patients treated with chemotherapy alone.
Vectibix® Improves Survival in Patients with Wild-Type KRAS
In 2014 the FDA approved Vectibix for use in combination with FOLFOX (leucovorin-fluorouracil-Eloxatin® [oxaliplatin]), as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.
Another study, which compared Vectibix plus best supportive care with best supportive care alone found that Vectibix significantly extends overall survival, the primary focus (or endpoint) of the trial. In addition, Vectibix has extended progression-free survival, a secondary endpoint of the study.
Second Line Vectibix Treatment of Advanced CRC
To evaluate the effectiveness of Vectibix in the second-line treatment of metastatic colorectal cancer, researchers conducted a Phase III clinical trial among 1,186 previously treated patients.(3) Study participants were assigned to receive treatment with FOLFIRI chemotherapy alone or FOLFIRI plus Vectibix.
- Among patients without KRAS mutations, progression-free survival was 5.9 months among patients treated with chemotherapy plus Vectibix compared with 3.9 months among patients treated with chemotherapy alone. Overall survival was 14.5 months among patients treated with chemotherapy plus Vectibix versus 12.5 months among patients treated with chemotherapy alone, but this result did not meet the criteria for statistical significance, suggesting that it could have occurred by chance alone.
- Among patients with KRAS mutations, the addition of Vectibix did not improve progression-free or overall survival.
In both studies, side effects of Vectibix included skin rash, low magnesium levels, and diarrhea.
These studies indicate that the addition of Vectibix to chemotherapy delays cancer progression among patients with either newly diagnosed or previously treated metastatic colorectal cancer. Because the benefit only applies to patients whose cancer does not contain a KRAS mutation, these studies also highlight the importance of KRAS testing prior to treatment with this type of targeted therapy.
Managing Vectibix Side Effects
Early Skin Treatment Reduces Skin Reactions in Colorectal Cancer Patients Treated with Vectibix®
The main side effects associated with Vectibix are skin reactions. These reactions can be mild to severe and often adversely affect a patient’s quality of life. Researchers have been evaluating ways to minimize these side effects.
Researchers from several institutions in the United States conducted a trial, referred to as the STEPP trial, which compared two different approaches aimed at minimizing skin reactions associated with treatment with Vectibix.
This trial included nearly 100 patients with advanced, recurrent colorectal cancer who were treated with Vectibix plus a Camptosar® (irinotecan)-based chemotherapy regimen. Patients were divided into two groups: one group received preemptive skin treatment, which started the day before beginning therapy and continued through the sixth week of therapy, while the other group received reactive treatment, which was administered anytime during the six weeks of therapy if the healthcare provider felt that side effects of the skin necessitated therapy.
Skin treatment included skin moisturizer (applied to the entire body, except stomach and legs, every morning), sunscreen (applied to exposed skin areas prior to being outdoors), topical steroid (applied to entire body, except stomach and legs, at bedtime), and the antibiotic doxycycline. Upon the seventh week of treatment, patients had the option to continue skin treatment.
- Only 29% of patients experienced serious skin reactions in the preemptive group compared with 62% in the reactive treatment group.
- The effectiveness of Vectibix/chemotherapy was not affected by preemptive skin therapy.
- Median progression-free survival was 4.9 months for patients in the pre-emptive skin therapy group and 4.3% for patients in the reactive skin therapy group.
- Median overall survival was approximately 13.5 months for both groups of patients.
- As with other EGFR inhibitors, patients without KRAS mutations had improved outcomes compared with those who had KRAS mutations.
The researchers concluded that preemptive therapy for skin reactions appears to significantly reduce the rate of skin reactions associated with treatment with Vectibix among colorectal cancer patients without affecting the therapy’s effectiveness. Patients who are to undergo therapy including Vectibix may wish to speak with their physician regarding their individual risks and benefits of preemptive skin therapy.
What do other studies show?
Vectibix is Not Inferior to Erbitux in Wild-Type KRAS Metastatic Colorectal Cancer
Vectibix® was non-inferior to Erbitux® for overall survival in the treatment of wild-type KRAS metastatic colorectal cancer in patients who have not responded to chemotherapy, according to the results of a study presented at the ESMO 2013 Congress of the European Society for Medical Oncology in Amsterdam.
This phase III trial included 999 patients with chemo-resistant wild-type KRAS metastatic colorectal cancer who were randomized to receive Vectibix or Erbitux. The prospective study showed that the median overall survival for patients treated with Vectibix was 10.4 months compared to 10 months for patients treated with Erbitux. Progression-free survival was a median of 4.1 months in patients treated with Vectibix versus 4.4 months in patients treated with Erbitux. Objective response rate, which is the percentage of patients who experienced tumor size reduction, was 22 percent for patients treated with Vectibix compared to 19.8 percent for patients treated with Erbitux.
In the safety analysis, the profiles of both treatments were consistent with previously reported studies. Adverse events (AEs) included known events such as rash, low levels of magnesium in the blood and infusion reactions.
The researchers concluded that Vectibix was non-inferior to Erbitux for the treatment of chemo-resistant wild-type KRAS metastatic colorectal cancer.
- Douillard J-Y, Siena S, Cassidy J et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. Journal of Clinical Oncology [early online publication]. October 4, 2010.
- Results From Phase 3 Trial Show Vectibix® (Panitumumab) Improves Overall Survival In Chemorefractory Wild-Type KRAS Metastatic Colorectal Cancer Versus Best Supportive Care [press release]. Amgen website. Available at: . Accessed August 3, 2015.
- Amado RG, Wolf M, Freeman D et al. Analysis of KRAS mutations in patients with metastatic colorectal cancer receiving panitumumab monotherapy. Presented at ECCO-14 – The European Cancer Conference. Barcelona, Spain, September 23-27, 2007. Abstract 0007.
- National Comprehensive Cancer Network. NCCN Updates Guidelines for Colorectal Cancer. Available at: . Accessed November 2008.
- Peeters M, Price TJ, Cervantes A et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. Journal of Clinical Oncology [early online publication]. October 4, 2010.
- Mitchell E, LaCouture M, Shearer H, et al. Updated Results of STEPP, a Phase 2, Open-Label Study of Pre-Emptive Versus Reactive Skin Toxicity Treatment in Metastatic Colorectal Cancer (mCRC) Patients Receiving Panitumumab + FOLFIRI or Irinotecan-Only Chemotherapy as Second-Line Treatment. 10th World Congress on Gastrointestinal Cancer. June 2008. Barcelona, Spain.
- Price T, Peeters M, Kim TW, et al. ASPECCT: a randomized, multicenter, open-label, phase 3 study of panitumumab (pmab) vs cetuximab (cmab) for previously treated wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Presented at the 38th Congress of the European Society for Medical Oncology (ESMO), Amsterdam, Netherlands, September 27-October 1, 2013. Abstract 18.