Cancer Treatment Today » New Drugs

Sprycel for colon cancer – pro

M Levin, MD — Fri, 02 Nov 2012 12:54:21 +0000

Dasatinib, also known as Sprycel, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. It is a drug that is approved by the FDA for chronic myelogenous leukemia. It has an effect on the Src kinases, which interact with the EGFR receptor. One phase II trial(Nautiyal et al) showed that Dasatinib is inactive in previously treated metastatic colorectal patients patients. There is a trial that is studying this drug: Dasatinib in Treating Patients With Previously Treated Metastatic Colorectal Cancer, NCT00504153. This study is ongoing, but not recruiting participants.

An interesting report suggested that curcumin, a turmeric derivative, can increase the effectiveness of Sprycel in colon cancer but this needs to be proven in large, prospective trials.

G. Somlo, F. Atzori, L. Strauss, A. Rybicki, X. Wu, W. Gradishar, J. Specht;Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004.J Clin Oncol 27:15s, 2009 (suppl; abstr 1012)

Lisa Hutchinson Targeted therapies: Dasatinib sensitizes KRAS-mutant colorectal cancer tumors to cetuximab Nature Reviews Clinical Oncology 8, 193 (April 2011)

Nautiyal J, Banerjee S, Kanwar SS, Yu Y, Patel BB, Sarkar FH, Majumdar AP. Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells.Int J Cancer. 2011 Feb 15;128(4):951-61.

For Lay version see here

Xeliri second line for metastatic colorectal cancer – pro

M Levin, MD — Sun, 23 Sep 2012 17:48:36 +0000

The issue that we will discuss is Xeliri (Xeloda and irinotecan) in second or later line of therapy. It is a tempting regimen because Xeldoa is an generally effective drug for colorectal cancer and it is oral. We start by pointing out that there are now six different classes of drugs with significant antitumor activity in colon cancer:

The best way to combine and sequence all of these drugs to optimize treatment is not yet established, although for intial treatment of metasatic colorectal cancer NCCN recommends combinations of 5FU and Lekovorin with oxaliplatin or irinotecan with or without Avastin, CAPEOX, 5FU/Leukovorin, Xeloda and Avastin or Folfoxiri.

For second or third line therapy, single agents are acceptable and NCCN lists irinotecan as a single agent. It also lists combinations, see p. COL-C of the NCCN guideline for colon cancer. NCCN has a complex schema when to give what for second line and also lists irinnotecan or Folfiri with Erbitux, Zaltrap or Vectbix. However, it does not list irinotecan with Xeloda.

NCCN, Colon cancer 2012

Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29:2011.

Ogino S, Shima K, Meyerhardt JA, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 2012; 18:890.

Bokemeyer C, Cutsem EV, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012.

Braun MS, Richman SD, Quirke P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008; 26:2690.

Boige V, Mendiboure J, Pignon JP, et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol 2010; 28:2556.

Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007; 12:38.

Masi G, Vasile E, Loupakis F, et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst 2011; 103:21.

For Lay version see here

Afinitor for colon cancer – pro

M Levin, MD — Fri, 21 Sep 2012 18:05:46 +0000

Evidence for using Afinitor for colorectal cancer is weak – one small trial with weak results. There is some evidence from a small trial ( Altomare et al) reported in ASCO 2012 that some colorectal cancer patients whose tumors had gotten worse on all standard treatments can benefit from a combination of Afinitor® (everolimus) and Avastin® (bevacizumab). This was a small trial in 50 patients. It showed a tumor control rate of 47%. Median progression-free survival time was 2.28 months, median overall survival time was 7.87 months. 46 percent of patients had disease control that lasted a median of 6.1 months. There were no complete or partial responses. 8 had a minor response lasting median 4.1 months. 15 had stable disease lasting median 6.7 months.

Altomare et al., 2010 ASCO Annual Meeting Abstracts, Abstract # 3535, Phase II trial of bevacizumab (B) plus everolimus (E) for refractory metastatic colorectal cancer (mCRC).

nccn. colorectal cancer 2012

Afinitor, Prescribing Information 2012.

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New drug: Zaltrap – pro

M Levin, MD — Fri, 24 Aug 2012 16:52:25 +0000

Zaltrap was approved by the FDA in the beginning of August 2012 for patients who fail oxaliplatin. It is also known as aflibercept, VEGF trap or, when used for macular degeneration, Eylea. It is a recombinant fusion protein between the Fc portion of human IgG1 and the extracellular domains of VEGF receptor 1 & 2 (VEGFR 1 & VEGFR 2), which binds VEGF-A and VEGF-B (vascular endothelial growth factor), as well as PLGF (placental growth factor). By binding to and inhibiting these angiogenic growth factors, their neovascular activity, and vascular permeability, ziv-aflibercept inhibits tumor angiogenesis.

Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. The approval for colon cancer was based on a phase III trial. ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Aflibercept failed its primary endpoint of overall survival in the Vital phase III trial for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), although it improved the secondary endpoint of progression-free survival. It is also in trials for prostate cancer.

J. Tabernero, E. Van Cutsem, R. Lakomy, J. Prausova, P. Ruff, G. Van Hazel, V. Moiseyenko, D. Ferry, J. McKendrick, K. Soussan-Lazard, E. Boelle, C. Allegra. VELOUR, a Phase 3 Study of Aflibercept (A) Versus Placebo (pbo) in Combination with FOLFIRI for the Treatment of Patients (pt) with Previously Treated Metastatic Colorectal Cancer (MCRC). 2011 European Multidisciplinary Congress. Abstract 6LBA. Presented September 25, 2011.

Tzu-Fei Wang and Albert Craig Lockhart Aflibercept in the Treatment of Metastatic Colorectal Cancer Clin Med Insights Oncol. 2012; 6: 19–30.

Tang P, Cohen SJ, Bjarnason GA. Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer (MCRC): a PMH phase II consortium trial. J Clin Oncol. 2008;(Suppl 26):Abstr 4027.

Teng LS, Jin KT, He KF, Zhang J, Wang HH, Cao J. Clinical applications of VEGF-trap (aflibercept) in cancer treatment. J Chin Med Assoc. 2010;73:449–56.

Please see the Lay version here

Chemo Options for Later Lines of Therapy for Metastatic Colon Cancer – pro

M Levin, MD — Sat, 04 Aug 2012 19:25:40 +0000

There are now five different classes of drugs with significant antitumor activity in colon cancer:

Fluoropyrimidine (5-fluorouracil [5-FU] which is usually given with leucovorin [LV], capecitabine, tegafur plus uracil [UFT]). Irinotecan, Oxaliplatin, Cetuximab and panitumumab. The latter two are monoclonal antibodies (MoAbs) directed against the epidermal growth factor receptor (EGFR), and bevacizumab, is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Recently another antibody was approved for colon cancer - Zaltrap, as well as the drug Stivarga. The best way to combine and sequence all of these drugs to optimize treatment is not yet established, although for intial treatment of metasatic colorectal cancer NCCN recommends combinations of 5FU and Lekovorin with oxaliplatin or irinotecan with or without Avastin, CAPEOX, 5FU/Leukovorin, Xeloda and Avastin or Folfoxiri.

For second or third line therapy, single agents are acceptable but NCCN lists only irinotecan as a single agent. It also lists combinations of these drugs, Erbitux and Vectbix(for wild type KRA patients), see p. COL-C of the NCCN guideline for colon cancer. NCCN has a complex schema when to give what for second line and also lists Erbitux and Vectbix. However, capecitabine is also FDA approved as a single agent. NCCN does not list 5FU/Leikovorin but it can also be considered appropriate given the long history of its use for colorectal metastatic cancer and support from many older papers.

Recently, Stivarga was also approved. STIVARGA® (regorafenib) is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy.

NCCN, Colon cancer 2013

STIVARGA Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013.

Grothey A, Sobrero A, Siena S, et al; CORRECT Study Team. Results of a phase III randomized, double-blind, placebo-controlled multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Poster presented at: American Society of Clinical Oncology 2012 Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA.

Read the Layperson version here.