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Comparing Targeted Therapies for Wild-Type RAS Metastatic Colorectal Cancer

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Dive into data from the PARADIGM trial, comparing treatment options for left-sided primary tumors in wild-type RAS metastatic colorectal cancer.

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  • Overview

    PARADIGM is the first prospective head-to-head trial of Vectibix® (panitumumab) plus FOLFOX6 chemotherapy versus bevacizumab plus FOLFOX6 for wild-type RAS metastatic colorectal cancer patients with left-sided primary tumors. Explore the efficacy and safety data on Vectibix® with Dr. Jennifer Caudle and Dr. Matthew Dugan, a medical oncologist with New England Cancer Specialists in Scarborough, Maine.

  • INDICATIONS

    Vectibix® is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC):

    • As first-line therapy in combination with FOLFOX.
    • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

    Limitation of Use:
    Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

  • IMPORTANT SAFETY INFORMATION

    BOXED WARNING: DERMATOLOGIC TOXICITY

    Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe, NCI-CTC grade 3 and higher, in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)] 

    • In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

    • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for inflammatory and infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®.

    • Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®.

    • Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications.

    • Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2, exon 3, and exon 4 of either KRAS or NRAS.

    • Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

    • Additionally, in an exploratory subgroup analysis, OS was shorter in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

    • Progressively decreasing serum magnesium levels leading to severe (grade 3 to 4) hypomagnesemia occurred in up to 7% of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during treatment, and up to 8 weeks after completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

    • Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in post-marketing experience. Terminate the infusion for severe infusion reactions.

    • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

    • Fatal and non-fatal cases of interstitial lung disease and pulmonary fibrosis have been observed in patients with Vectibix®.

    • In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue therapy if interstitial lung disease is confirmed. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

    • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix®.

    • Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred with Vectibix® use. Monitor for evidence of keratitis, ulcerative keratitis, or corneal perforation. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis, ulcerative keratitis, or corneal perforation.

    • In the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3 to 5 adverse reactions. NCI-CTC grade 3 to 4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash and acneiform dermatitis, diarrhea, dehydration primarily occurring in patients with diarrhea, hypokalemia, stomatitis and mucositis, and hypomagnesemia.

    • NCI-CTC grade 3 to 5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients and included fatal events in three Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent over the first 24 weeks on study compared to those randomized to bevacizumab and chemotherapy.

    • Vectibix® can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use contraception during treatment and for at least 2 months after the last dose of Vectibix®.

    • In monotherapy, the most commonly reported adverse reactions, greater than or equal to 20%, in patients with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

    • The most commonly reported adverse reactions, greater than or equal to 20%, with Vectibix® + FOLFOX were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions, greater than or equal to a 2% difference between treatment arms, were diarrhea and dehydration.

    Please see Vectibix® full Prescribing Information, including Boxed WARNING.

    Reference: 
    Watanabe J, Muro K, Shitara K, et al. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023;329:1271–1282. doi:10.1001/jama.2023.4428

    ©2023 Amgen Inc. All rights reserved. USA-954-80447 7/23

Schedule20 Jul 2024