New drug combinations and dosing schedules improve outlook in advanced colon cancer

By Dr. Liji Thomas, MDJul 8 2019

Advanced colon cancer often spreads widely and may not respond to standard chemotherapy. In such a case, a novel combination of drugs and flexible dosing may help achieve a better outlook, as demonstrated by several new studies.

In one study, investigators explored the use of paclitaxel in the treatment of metastatic squamous cell carcinoma of the anus. A 5-fluorouracil (5-FU)/cisplatin combination is the current first-line treatment for metastatic disease, but no standard therapy exists for refractory tumors (resistant to standard therapy). In this scenario, 6 patients were treated with paclitaxel, which is used in similar tumors of the head and neck. There was a measurable response to weekly treatment with paclitaxel in 4 patients, while one more showed stabilization of the disease following this therapy.

The results of the European REARRANGE trial were presented at the ESMO World Congress on Gastrointestinal Cancer 2019. These were from almost 300 patients across Spain, Italy and France. These patients were 64 years old, on average, and all had refractory metastatic colorectal cancer (mCRC). All had progressed from first-line through fourth-line treatment for the disease.

Regorafenib is a multi-kinase inhibitor used in refractory mCRC but with an unacceptably high rate of discontinuation due to severe adverse effects. The trial aimed to assess the effect of changes in the dosing schedule on the tolerability, toxicity and overall survival with this drug.

Patients were randomly allocated to one of three groups: standard dose (SD), reduced dosing (RD) and intermittent dosing (ID). SD patients received 160 mg/day, while RD patients were on 120 mg/day, both for three weeks followed by a week off. In the ID group, regorafenib at 160 mg/day was used over alternate weeks.  

If cycle 1 of RD and ID treatment was tolerated well, all patients were switched to SD cycles thereafter. Guillem Agiles, study author, explains, “We reduced the dose in the first cycle and then escalated because it has been shown that the toxicity is higher in the first and second months of treatment."

While there was no change in the overall number of grade 3/4 adverse events, RD and ID use in the first couple of months was numerically associated with fewer adverse events that led to discontinuation, such as fatigue, hypertension and hand-foot skin reaction (HFSR. Treatment duration and median progression-free survival (about 3-4 months and 2 months respectively) were not affected, making this a viable alternative.  The trial, which is the largest so far in this area, thus supported the use of flexible dosing with regorafenib in this condition.

Agiles explains, “These results, interpreted in the context of other trials, like the American study ReDOS (3), tell us that the more flexible doses of regorafenib are an effective alternative in order to improve quality of life in patients with metastatic refractory colorectal cancer". Other oncologists were equally impressed, with University Leuven professor Eric Van Cutsem predicting that it would change the way regorafenib is used in mCRC.

The ESMO congress also heard of another breakthrough: the BEACON CRC study on a combination of three drugs used to treat refractory mCRC positive for BRAF V600E-mutation.  This mutation is observed in 15% of mCRC patients and has a poor prognosis.

The trial involved 665 patients in three treatment groups: triplet therapy with encorafenib, binimetinib and cetuximab; doublet therapy with encorafenib and cetuximab; and one of two chemotherapeutic regimens (irinotecan or a combination of folinic acid, fluoruracil and irinotecan (FOLFIRI) with cetuximab).

The triplet combination of non-chemotherapy agents was worked out to suppress both the BRAF kinase pathway and other compensatory mechanisms that allow tumor cells to develop resistance to BRAF inhihibitors. Study author Scott Kopetz commented: “Colorectal cancer does not respond to BRAF therapy alone because tumour cells adapt through other mechanisms after initial treatment. With this triple targeted therapy, we are using a very scientifically logical combination to inhibit BRAF and these other mechanisms.”

The triplet therapy was well tolerated, and resulted in a median overall survival of 9 months, and objective response rate of 26% as against 5.4 months and 2% respectively with standard therapy. The striking improvement caused one expert to stress the need for routine BRAF testing in all patients with CRC henceforth, making this the new standard of care. “We now have a specific treatment that can change the natural course of the disease in patients with BRAF mutations and is better than previous therapy, so it is essential that patients are routinely tested,” said professor Andres Cervantes of Valencia.

Moreover, the avoidance of chemotherapy is a big bonus. Cervantes says, “In many other types of cancer, and particularly in colorectal cancer, it is common for biological targeted therapies to be used in combination with chemotherapy. The fact that we can give this targeted combination without the need for chemotherapy is very good news for patients, not least because of the side effects that they typically experience with chemotherapy.”

While only refractory mCRC patients who have failed up to two lines of chemotherapy are presently eligible for such treatment, it needs to be studied in other BRAF-mutant tumors, whether in earlier mCRC or adjuvant therapy following primary excision of the tumor, to enhance cure rates.

The final word? Changing drug combinations and dosing schedules promise to make life better for mCRC patients while maintaining treatment efficacy.