New Developments in Oral Targeted Agents for Advanced Colorectal Cancer

Axel Grothey, MD

In September 2012, the FDA approved regorafenib (Stivarga) as a salvage treatment for metastatic colorectal cancer (mCRC) previously treated with chemotherapy, an antivascular endothelial growth factor (VEGF) therapy, or an anti-epidermal growth factor receptor (EGFR) therapy. Regorafenib had received a fast-track FDA review status and was approved after only a three-month review process. The drug is the first targeted oral therapy to receive an FDA approval for treatment of advanced CRC, and the second drug to be approved for mCRC in 2012.

Although progress has been made in treating colorectal cancer, including the development of biologic agents that target EGFR and angiogenesis, the median survival in mCRC remains about two years. The five-year survival rate for a patient with stage II CRC is approximately 50%, but for stage IV it is only 6%, according to the American Cancer Society. It is estimated that nearly 52,000 men and women died of colorectal cancer in the United States in 2012, according to the National Cancer Institute.

Regorafenib was approved based on the results of the phase III CORRECT trial, which demonstrated an improved median overall survival (OS) of 1.4 months versus placebo in patients with mCRC that had progressed on previous therapy. The results were initially presented at the annual American Society of Clinical Oncology (ASCO) meeting in June 2012,1 and updated survival data were subsequently presented at the annual European Society for Medical Oncology (ESMO) meeting in September/ October 2012.2 The full trial results have been published in The Lancet.3

The CORRECT trial randomized 760 patients in a 2:1 ratio to receive either 160 mg of once-daily regorafenib plus best supportive care or placebo plus best supportive care. Patients all were previously treated for mCRC with either oxaliplatin-, irinotecan-, or fluoropyrimidine- based chemotherapy or with bevacizumab. Median OS was 6.4 months in the regorafenib arm compared with 5.0 months in the placebo arm (P =.0052). The OS rate at 12 months was 24.1% in the regorafenib arm compared with 17% in the placebo arm. The median progressionfree survival (PFS) was 2.0 months in the experimental arm compared with 1.7 months in the placebo arm (P <.0001). Regorafenib reduced the risk of progression by 51%.

&ldquo;I think many oncologists are adopting the use of regorafenib,&rdquo; said Randall F. Holcombe, MD, professor of Medicine, Hematology and Oncology at Mount Sinai Hospital and deputy director of the Tisch Cancer Institute in New York City. &ldquo;We have many patients who have progressed on all standard therapies. [The drug is a good option], especially for those whose tumors harbor a KRAS mutation, who are not candidates for EGFR antibody therapy, but who still have a good performance status and are looking for additional treatment options.&rdquo;

&ldquo;Regorafenib is not a drug without toxicities,&rdquo; said Holcombe. &ldquo;Patients can have fatigue, fever, rash, including a hand-foot syndrome, mucositis, diarrhea, fluid retention and anorexia.&rdquo; Treatment-related toxicities occurred in the vast majority, 93%, of patients on regorafenib therapy. Serious side effects included hepatotoxicity, hemorrhage, and gastrointestinal perforation.

According to Axel Grothey, MD, of the division of Medical Oncology at the Mayo Clinic in Rochester, Minnesota, and lead author of the CORRECT trial, it is sometimes difficult to decide if the symptoms experienced on therapy are truly drug- or tumor-related. Grothey noted that side effects on regorafenib tend to occur within the first two weeks of treatment, when patients should be closely monitored.

New Targets, New Drugs in Development

Regorafenib is a multikinase inhibitor that targets various intracellular and membrane-associated kinases involved in angiogenic, stromal, and oncogenic signaling. Its targets include VEGFR1 and 2, KIT, FGFR1 and 2, BRAF, and the Abl kinase.As data on the genetic basis of CRC accumulate, new treatment targets are emerging. For example, the BRAF kinase is mutated in 5% to 10% of mCRC. An extensive analysis of 276 colon and rectal tumors by The Cancer Genome Atlas Network confirmed genetic targets and identified novel genes frequently mutated, as well as chromosomal rearrangements and amplifications.4 KRAS and PIK3CA, the phosphatidylinositide 3-kinase catalytic subunit of the PI3 kinase, were both identified among the eight most frequently mutated genes in either colon or rectal tumors.

Oral Kinase Inhibitors in Development

Such detailed analyses continue to lead to a better understanding of the important genes and pathways involved in CRC development and progression. This knowledge is facilitating not only the development of new targeted agents, but also allowing for risk stratification based on molecular subtypes and molecular predictors of response to therapies.Several oral tyrosine kinase inhibitors (TKIs) are currently in development for advanced CRC. Cediranib, an oral inhibitor of VEGF kinase, has been tested in a phase III trial in combination with chemotherapy for first-line mCRC in comparison with bevacizumab plus chemotherapy. The HORIZON III trial5 demonstrated that cediranib was similar to bevacizumab in terms of OS and PFS. Unfortunately, the study also found that cediranib was associated with worse patient-reported outcomes, resulting in interruption of treatment, noted Holcombe.

Trials with other TKIs are still awaiting results. Tivozanib, also an oral VEGF inhibitor, is currently in a phase II trial in combination with chemotherapy versus bevacizumab in patients with treatment-na&iuml;ve mCRC. Apatinib, an oral, selective inhibitor of the VEGF receptor- 2 is being tested as a monotherapy for advanced CRC.

&ldquo;Any of these oral tyrosine kinase inhibitors may have an advantage over bevacizumab, although it is not clear which if any will prove to be superior to bevacizumab yet,&rdquo; said Holcombe. &ldquo;The oral mode of administration is appealing if the toxicity profile is not worse than that of bevacizumab.&rdquo;

Regorafenib is being tested both in the first- and second-line CRC setting in combination with chemotherapy. Grothey sees regorafenib moving into these earlier treatment settings. Currently, bevacizumab is the most frequently used biologic agent in advanced CRC.

Other Targeted Agents

These TKIs are promising, but not as add-on therapies to standard firstline chemotherapy FOLFOX, which is &ldquo;a graveyard for many interesting agents,&rdquo; Grothey said. Instead, he believes that regorafenib should be tested as a maintenance monotherapy after first-line induction with chemotherapy.Several oral agents that target the PI3K pathway are in phase I development for cancers that include advanced CRC. These include BKM120, a specific class I PI3K inhibitor, and DS-7423, a dual inhibitor of PI3K and mammalian target of rapamycin (mTOR) kinase. &ldquo;Combinations of inhibitors targeting the MAP kinase pathway, including BRAF and MEK along with PI3K inhibitors, are promising,&rdquo; said Grothey.

Prognostic and Predictive Biomarkers

Holcombe agrees. &ldquo;I think agents targeting the PI3K/AKT signaling pathway are potentially especially promising,&rdquo; he said. &ldquo;These agents will likely need to be combined with either traditional chemotherapy or other biologics for maximal effectiveness because of redundancy in signaling pathways,&rdquo; Holcombe added.Many clinical trials for CRC now include biomarker analyses as part of the drug development. For example, it has been known for some time that those patients whose CRC tumor harbors a mutation in the KRAS gene do not respond to treatment with cetuximab, an anti-EGFR antibody. About 30% to 50% of patients with CRC have a KRAS mutation. The FDA has recently approved a polymerase chain reaction (PCR)- based screening test to determine the KRAS mutation status of a CRC tumor. The test recognizes seven frequent mutations in the KRAS gene.

Mutations in the BRAF gene also are a likely predictor of nonresponse to anti-EGFR therapy. Many other molecular biomarkers are still in early development awaiting clinical validation testing. For antiangiogenesis therapy, there is not likely to be a single marker that can predict response to treatment, Grothey said. If any biomarkers are identified, they will likely be quantitative, generating a predictive value score on a continuous scale.

&ldquo;Angiogenesis is a very complicated process involving signals from the tumor cells, but also from the stromal cells in the tumor microenvironment,&rdquo; said Holcombe. &ldquo;The process also involves the ability of endothelial cells in this tumor environment to respond to a variety of signals.&rdquo; This is one reason that simple biomarkers, particularly molecular biomarkers, are not likely for antiangiogenesis therapy.

Many more studies are needed to understand how molecular mutations can dictate either response or resistance to a targeted therapy. A molecular mutation or genotype is not always associated with a particular treatment response or phenotype because of the complexity of the genetics of CRC. Datasets such as that created by The Cancer Genome Atlas Network will continue to serve as tools for both the creation of new therapies and for predictive and prognostic biomarker approaches. Furthermore, analyses of epigenetic alterations and other layers of complexity will need to be integrated for a full understanding of what drives colorectal cancer.

References

1. Van Cutsem E, Sobrero AF, Siena S, et al. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC).J Clin Oncol. 2012;30 (suppl; abstr 3502).
2. Van Cutsem EJD, Grothey A, Laeuven BE. Phase 3 CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC): overall survival update. Presented at: 38th European Society for Medical Oncology (ESMO) Congress; September 28-October 2, 2012; Vienna Austria.Ann Oncol. 2012;23(suppl 9; abstr LBA18).
3. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.The Lancet. 2013;381(9863): 303-312.
4. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer.Nature. 2012;487(7407): 330-337.
5. Schmoll HJ, Cunningham D, Sobrero A, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a doubleblind, randomized phase III study (HORIZON III).J Clin Oncol. 2012;30(29):3588-3595.