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 FDA has approved Suflave (Sebela/Braintree), a low-volume polyethylene glycol (PEG)- and sulfate-based product for cleansing of the colon prior to colonoscopy in adults. Other oral colonoscopy preparations available in the US are listed in Table 2. Suflave is marketed as tasting better than other products.

The FDA has approved an oral tablet formulation of sodium sulfate, magnesium sulfate, and potassium chloride (Sutab – Braintree) for colon cleansing prior to colonoscopy in adults. A sodium sulfate-based oral solution (Suprep) has been available in the US since 2010. Sutab is the second tablet formulation to be approved for bowel cleansing prior to colonoscopy; a sodium phosphate-based tablet (OsmoPrep) was approved earlier.

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.

In our article in issue 1564 on Plenvu for colonoscopy preparation (Med Lett Drugs Ther 2019; 61:11), the comparator drug in the DAYB trial was not Prepopik, but rather Citrafleet, a similar sodium picosulfate-based preparation that is not available in the US. Also, we said that Plenvu can be taken as a single- or split-dose regimen; we should have said that it can be taken as two doses in a single day or split over two days.

Most colorectal cancers arise from localized adenomatous polyps in a process that may take 10 years or more. Early detection and removal of a precancerous colonic lesion (polyp) can prevent cancer from developing.

The FDA has approved Plenvu (Salix), a polyethylene glycol (PEG)-containing oral powder for reconstitution, for colon cleansing prior to colonoscopy in adults. Plenvu is the first PEG-containing colonoscopy preparation that requires only 1 L of water for dissolution and ingestion of 1 L of clear fluid in addition.

The FDA has approved Clenpiq (Ferring), a low-volume oral solution that contains sodium picosulfate, magnesium oxide, and anhydrous citric acid, for colon cleansing prior to colonoscopy in adults. The ready-to-drink solution contains the same ingredients as Prepopik, which is supplied as a powder for reconstitution.

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.

Download complete U.S. English article

The FDA has approved the pyrimidine analog uridine triacetate (Vistogard – Wellstat Therapeutics) for emergency treatment of a fluorouracil (5-FU) or capecitabine (Xeloda, and generics) overdose or severe toxicity that occurs within 96 hours following administration of one of these drugs. Fluorouracil is a cytotoxic antimetabolite used to treat breast, colorectal, and other cancers; capecitabine is an oral prodrug of fluorouracil.

Uridine triacetate, a prodrug, is deacetylated to uridine after oral administration. Excess circulating uridine is converted into uridine triphosphate, which inhibits the cytotoxic activity of 5-fluorouridine triphosphate, a fluorouracil metabolite, by competing with it for incorporation into RNA.

FDA approval was based on two unpublished open-label studies (summarized in the package insert) in a total of 135 adults and children with overdoses of fluorouracil or capecitabine (n=117) or severe or life-threatening toxicities within 96 hours after their administration (n=18). The overall survival rate at 30 days was 96%. In retrospective case reports that included 25 patients who received only supportive care after a fluorouracil overdose, the survival rate was 16%.

Vistogard is supplied as orange-flavored oral granules in single-dose packets containing 10 grams of uridine triacetate. The granules should be mixed with 3-4 ounces of soft food and taken every 6 hours for 20 doses. The recommended dose is 10 grams for adults and 6.2 grams/m² (10 grams maximum) for children. Mild to moderate nausea, vomiting, and diarrhea have been reported. The cost for one course of treatment is $75,000.1

1. Approximate WAC. 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. June 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

Download complete U.S. English article

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.

Download complete U.S. English article

The FDA has approved Cologuard (Exact Sciences), a stool DNA test, to screen average-risk adults ≥50 years old for colorectal cancer.

Regorafenib (Stivarga – Bayer), a multikinase inhibitor, has been approved by the FDA for treatment of patients with metastatic colorectal cancer previously treated with multiple other regimens specified in the labeling. It has also been approved for use in treatment-refractory, locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST).

Ziv-aflibercept (Zaltrap – Sanofi/Regeneron), a vascular endothelial growth factor (VEGF) inhibitor, has been approved by the FDA for use in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) for treatment of metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. It is the same drug as aflibercept, which was approved last year as an intravitreal injection (Eylea) for treatment of neovascular (wet) agerelated macular degeneration (AMD). Ziv-aflibercept is the second VEGF inhibitor approved for treatment of metastatic colorectal cancer; bevacizumab (Avastin), given in addition to chemotherapy, is a standard firstand second-line therapy.

Colonoscopy remains the preferred method of colorectal cancer screening. Many patients consider cleansing the bowel in preparation for colonoscopy the most unpleasant part of the procedure, but inadequate bowel preparation significantly lowers the diagnostic yield.

Use of screening tests to identify cancers before they cause symptoms can lead to earlier therapy and may improve outcomes. Screening tests for some common cancers are reviewed below.

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.

The FDA has approved a new genetic test to identify patients who may be at increased risk of severe toxicity when treated with the cancer chemotherapy drug irinotecan (Camptosar). The Invader UGT1A1 Molecular Assay (Third Wave Technologies) detects the UGT1A1*28 allele, a variation in the uridine diphosphate glucuronosyltranferase 1A1 (UGT1A1) gene. The FDA recently revised the safety labeling for irinotecan, recommending that the dosing of irinotecan be reduced for patients who are homozygous for the UGT1A1*28 allele.

Currently available techniques for colorectal cancer screening include fecal occult-blood testing, flexible sigmoidoscopy, double contrast barium enema (DCBE) and traditional optical colonoscopy. Optical colonoscopy requires bowel cleansing and sedation, and involves some risk, but is generally accepted as the best available method for detection of lesions and offers the advantage that polyps can be removed when they are identified. A less invasive screening tool, computed tomography (CT) colonography, also known as virtual colonoscopy (VC), offers an additional option.

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.

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).

Irinotecan hydrochloride (Camptosar - Pharmacia & Upjohn; formerly CPT-11) has been approved by the US Food and Drug Administration for treatment of metastatic colorectal cancer refractory to other drugs including fluorouracil (5-FU; Adrucil and others).