The RAS GTPase family inhibitor adagrasib (Krazati – BMS), which received accelerated approval for treatment of KRAS G12C (glycine-to-cysteine mutation at codon 12)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in 2022, has now received accelerated approval from the FDA for use with cetuximab for treatment of KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) in adults who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Adagrasib is the first KRAS inhibitor to be approved in the US for treatment of CRC.

The FDA has approved the oral kinase inhibitor encorafenib (Braftovi – Pfizer), in combination with the epidermal growth factor receptor (EGFR) inhibitor cetuximab (Erbitux), for treatment of adults with metastatic colorectal cancer (CRC) with a BRAF V600E mutation. Encorafenib was approved in 2018 for use with the mitogen-activated kinase (MEK) inhibitor binimetinib (Mektovi) for treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

The FDA has approved Lonsurf (Taiho Oncology), a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil, for oral treatment of metastatic colorectal cancer. Trifluridine is incorporated into DNA, interfering with DNA synthesis and inhibiting cell proliferation. Tipiracil inhibits the metabolism of trifluridine. The combination is only approved for use in patients who were previously treated with a fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF biological such as bevacizumab, and, if the tumor is RAS wild-type, an anti-EGFR agent (cetuximab or panitumumab). The median survival of patients with metastatic colorectal cancer treated with these drugs is about 30 months.

FDA approval of trifluridine/tipiracil was based on the results of a randomized, double-blind, placebo-controlled trial in 800 patients with metastatic colorectal cancer who had previously been treated with chemotherapy and biological therapy. Median overall survival, the primary endpoint, was significantly longer with trifluridine/tipiracil compared to placebo (7.1 months vs 5.3 months). Median progression-free survival, a secondary endpoint, was 1.7 months with placebo and 2.0 months with trifluridine/tipiracil. The most common adverse effects of the combination included nausea, vomiting, diarrhea, fatigue, neutropenia, anemia, and leukopenia. Among 533 patients treated with the combination, only one treatment-related death occurred (from septic shock).1

Lonsurf is available in tablets containing 15 mg of trifluridine and 6.14 mg of tipiracil or 20 mg of trifluridine and 8.19 mg of tipiracil. The recommended dosage is 35 mg/m² (based on the trifluridine component) orally twice daily on days 1-5 and 8-12 of each 28-day cycle until disease progression or unacceptable toxicity occurs. Lonsurf should be taken within one hour after meals. The cost of one treatment cycle (sixty 20 mg/8.19 mg tablets) is $10,947.70.2

1. RJ Mayer et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372:1909.
2. Approximate WAC for a patient with a 1.7 m² surface area. WAC = wholesaler acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. May 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth. com/policies/drug-pricing-policy.

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Panitumumab (Vectibix - Amgen), a fully human IgG₂ monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), has been approved by the FDA for treatment of patients with EGFR-expressing metastatic colorectal cancer that has progressed despite standard chemotherapy. It is the second monoclonal antibody EGFR inhibitor to be approved for metastatic colorectal cancer; cetuximab (Erbitux), a human-murine chimeric IgG₁ monoclonal antibody, was approved in 2004.

A variety of cancer chemotherapy drugs are used, mostly in combination, for treatment of locally advanced and metastatic esophageal, gastric and colorectal cancers. The mechanism of action, indications and adverse effects of some of these drugs are discussed in thei article.

Erlotinib (Tarceva) is the second oral epidermal growth factor receptor (EGFR) inhibitor to become available in the US for treatment of advanced refractory NSCLC. In clinical trials, erlotinib produced a response rate of only 8.9%, but increased median survival from 4.7 to 6.7 months. Patients who had never smoked and those with EGFR-positive tumors survived longer. Erlotinib is generally well tolerated; diarrhea and rash are the most common adverse effects.

Cetuximab (Erbitux - ImClone Systems/Bristol-Myers Squibb), an epidermal growth factor receptor (EGFR) inhibitor, and bevacizumab (Avastin - Genentech), the first vascular endothelial growth factor angiogenesis inhibitor, have recently been approved by the FDA for treatment of patients with metastatic colorectal cancer. Cetuximab is approved for treatment of patients with EGFR-expressing tumors, either in combination regimens with irinotecan (Camptosar)when the cancer has progressed on irinotecan-based therapy, or as monotherapy for those who cannot tolerate irinotecan. Bevacizumab is approved for first-line therapy in combination with a fluorouracil-based regimen.

The tables in this article list drugs used for treatment of cancer in the USA and Canada and their major adverse effects. The choice of drugs in Table I is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. In some cases, such as elderly patients or those with many co-morbid illnesses, the regimen of choice might not be suitable. For many of the cancers listed, surgery and/or radiation therapy may be the treatment of choice or may also be part of the management. Anticancer drugs and their adverse effects are listed in Table II on page 46. A partial list of brand names appears on page 52.