Safety data from the Dutch government-funded phase III CAIRO 2 trial combining two biologic drugs for colorectal cancer alongside two standard chemotherapy agents show no cause for concern say investigators. An interim safety analysis from the 755-patient study was presented this week at ECCO, the European Cancer Organisation conference in Barcelona.

Reasons for concern about combining biologic drugs stem from data emerging earlier this year in the PACCE trial. These showed adding Amgen’s EGFR inhibitor Vectibix (panitumumab) to Roche’s Avastin (bevacizumab) along with a three-drug chemotherapy regimen made patients worse off. Progression free and overall survival in PACCE were lower for patients adding Vectibix while drug toxicity was increased. The trial was stopped and Vectibix therapy was withdrawn from participants and as yet no firm explanation for the unexpected outcome has been found.

So far however, it appears that combining Merck Serono/ImClone’s Erbitux (cetuximab), an EGFR inhibitor with different characteristics to Vectibix, with Roche’s Avastin has no increased adverse effects other than producing a high incidence of skin rash. This is regarded more as a positive than an adverse effect since it indicates a good response to Erbitux and is associated with improved survival. The two biologics have already been shown to improve outcomes when used alongside irinotecan chemotherapy.

CAIRO 2 is comparing whether or not adding Erbitux to standard first line therapy of Avastin, capecitabine and oxaliplatin in mCRC makes a difference in keeping disease in check. The study’s primary endpoint is progression free survival whilst overall survival, response rates, toxicity and quality of life are secondary endpoints and efficacy data from CAIRO 2 will be presented next year.

The interim safety analysis from CAIRO 2 presented by Dr J Tol for the Dutch Colorectal Cancer Group looked at the first 389 evaluable patients of whom 192 received Erbitux on top of the three other drugs and 197 received the standard treatment alone. Unlike the PACCE trial experience, CAIRO 2 patients didn’t experience substantially more diarrhoea from adding an EGFR inhibitor (23% vs 20%) and dehydration and infections were not a problem, she said. Nausea and vomiting were slightly reduced in the Erbitux arm. Cardiovascular and haematological events were low and comparable in both study arms as were allergic reactions, bleeding and infections.

The strategy of combining the four drugs for previously-untreated advanced colorectal cancer patients looks safe and feasible, concluded Dr Tol.

Rising drug costs tackled by ECCO

CAIRO 2 may not be generating safety concerns but this and other studies combining biologic agents to produce superior survival will create an increasing dilemma for health care providers. Currently they are struggling to provide even one biologic agent for patients let alone two or three. Avastin costs $50,000 per patient per year for colorectal cancer but higher doses for breast and lung cancer can double the cost. Extending survival and remaining on treatment will mean costs per patient could soar.

An Italian centre is already doing a preliminary study of a three-biologic combination of Avastin, Erbitux and Novartis’ Glivec (imatinib) in colorectal cancer patients with unresectable metastases and seeing promising results. Only 20 patients have been recruited so far but of the 15 evaluable, 11 have shown a response and a third have been able to undergo surgery and have their tumours completely removed. Effectively resection of all disease equates to a cure.

“The successful development of many new anticancer drugs is challenging every health economic programme in Europe,” said ECCO President Professor John Smyth. “Improving cost-effectiveness, especially of drug therapies, is a major priority for industry, politicians and the public,” he stressed. ECCO will be asking governments and the European Commission to consider these issues as a matter of urgency.

The costs of providing new cancer drugs will soar even if their price comes down over the next 20 years. Cases are projected to rise by at least 50% with the rise in the ageing population, predicted cancer epidemiologist Professor Peter Boyle, Director of the International Agency for Research on Cancer based in Lyon, France. The rising proportion of older people will dramatically increase the cancer burden. This year there will be 11 million cancer diagnoses, seven million deaths and 25 million people living with cancer, he said. In 2030 there will be 27 million diagnoses, 17 million deaths and 75 million cancer survivors.