Zolbetuximab-clzb (Vyloy – Astellas), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, has been approved by the FDA for use in combination with fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma in patients who have CLDN18.2-positive tumors. It is the first monoclonal antibody to be approved in the US that selectively targets CLDN18.2.

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.

Fruquintinib (Fruzaqla – Takeda), an oral kinase inhibitor, has been approved by the FDA for treatment of adults with metastatic colorectal cancer (mCRC) who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, in patients with RAS wild-type mutations, anti-EGFR therapy. The drug can be used in patients with mCRC regardless of biomarker status. Fruquintinib is the first drug to become available in the US for treatment of mCRC that targets 3 VEGF receptor kinases.

The oral kinase inhibitor tucatinib (Tukysa – Seagen) has received accelerated approval from the FDA for use in combination with trastuzumab (Herceptin) for treatment of adults with RAS wild-type human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens. Tucatinib was approved in 2020 for use in combination with trastuzumab and capecitabine (Xeloda, and generics) for treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who received at least one prior anti-HER2-based regimen for metastatic disease.

The immune checkpoint inhibitor pembrolizumab (Keytruda – Merck), a programmed death receptor-1 (PD-1) inhibitor, has been granted accelerated approval by the FDA for use in adults and children who have unresectable or metastatic microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) solid tumors that have progressed following treatment, and do not have any satisfactory alternative treatment options. For metastatic colorectal cancer, the indication is limited to tumors that have progressed following combination treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This is the first approval of a cancer drug based solely on the presence of certain biomarkers, regardless of the organ in which the cancer originated or the histology of the tumor.

MSI-H and dMMR are markers for abnormalities in cancer cells that prevent DNA replication and postreplicative DNA repair.1 These biomarkers are found most commonly in cancers of the endometrium, stomach, and colon. The incidence of MSI-H or dMMR in these tumors appears to be lower in advanced disease than in early-stage disease; about 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.2

FDA approval was based on data from five unpublished, single-arm trials of pembrolizumab (summarized in the package insert) that included a total of 149 previously treated adults with various MSI-H or dMMR metastatic or unresectable tumors (90 patients had colorectal cancer). The overall objective response rate was 39.6% and the complete response rate was 7.4%. The median duration of response had not been reached by the end of the study; 78.0% of patients had a response duration of ≥6 months. Adverse reactions, including immune-mediated effects, were similar to those reported previously with pembrolizumab.

The recommended adult dosage of pembrolizumab for this indication is 200 mg IV (2 mg/kg up to a maximum of 200 mg for children) every 3 weeks for a maximum of 24 months. The cost for one adult dose is about $9162.3

Pembrolizumab was previously approved for treatment of unresectable or metastatic melanoma,4 metastatic non-small cell lung cancer (NSCLC), including nonsquamous NSCLC in combination with pemetrexed and carboplatin,5 recurrent or metastatic head and neck squamous cell carcinoma, refractory classical Hodgkin lymphoma, locally advanced or metastatic urothelial carcinoma,6 and recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

1. A Copija et al. Clinical significance and prognostic relevance of microsatellite instability in sporadic colorectal cancer patients. Int J Mol Sci 2017 Jan 6 (epub).
2. S Lemery et al. First FDA approval agnostic of cancer site - when a biomarker defines the indication. N Engl J Med 2017; 377:1409.
3. Approximate WAC. WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. December 5, 2017. Reprinted with permission by First Databank, Inc. All rights reserved. ©2017. www. fdbhealth.com/policies/drug-pricing-policy.
4. Pembrolizumab (Keytruda) for metastatic melanoma. Med Lett Drugs Ther 2014; 56: e114.
5. Pembrolizumab (Keytruda) for first-line treatment of metastatic NSCLC. Med Lett Drugs Ther 2017; 59:22.
6. Three more immune checkpoint inhibitors for advanced bladder cancer. Med Lett Drugs Ther 2017; 59:e202.

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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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The FDA has approved Akynzeo (Helsinn/Eisai), an oral fixed-dose combination of the substance P/neurokinin 1 (NK₁) receptor antagonist netupitant and the serotonin-3 (5-HT₃) receptor antagonist palonosetron, for prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy in adults. Akynzeo is the first product to combine drugs from these two classes. Palonosetron (Aloxi) is also available as a single agent for prevention of chemotherapy-induced and postoperative nausea and vomiting. Netupitant is the second substance P/NK₁ receptor antagonist to be approved in the US; aprepitant (Emend) was the first.

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.

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.

Aprepitant (Emend - Merck), the first substance P/neurokinin 1 (NK₁) receptor antagonist to be approved by the FDA, is now available for oral use with corticosteroids and selective serotonin (5-HT₃) receptor antagonists to prevent nausea and vomiting caused by highly emetogenic anticancer drugs such as cisplatin.

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.

Oxaliplatin (Eloxatin -Sanofi-Synthelabo) has been approved by the FDA for use in combination with fluorouracil (5-FU; Adrucil, and others) and leucovorin (LV; Wellcovorin) for patients with metastatic colorectal cancer whose disease has recurred or progressed despite treatment with 5-FU/LV plus irinotecan (Camptosar - Medical Letter 1997; 39:8).

The tables in this article list drugs used for treatment of cancer in the USA and Canada. The choices of drugs in Table 1 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. For many of the cancers listed, surgery and/or radiation therapy are also part of the management of the disease.