ASCO meeting 2009: current blockbusters advance standard care in new indications

The American Society of Clinical Oncology (ASCO) meeting is the year's largest single oncology event, playing host to leading industry figures as they demonstrate clinical data and discuss its implications going forward. This year's event focused on the personalization of cancer care and the proliferation of targeted therapies. Furthermore, the conference demonstrated the synergistic benefits of newer, established agents with conventional chemotherapy .

Lead investigator Professor Eric Van Cutsem presented inspiring data from a large, international Phase III trial of Herceptin (trastuzumab; Genentech/Roche/Chugai) in human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. The trial, named ToGA, represents the first randomized prospective Phase III trial targeting the HER2-positive gastric cancer population with Herceptin as a first-line therapy.

When combined with chemotherapy (5-fluorouracil, Xeloda [capecitabine; Genentech/Roche/Chugai] or cisplatin), Herceptin significantly improved overall survival to 13.8 months versus 11.1 months for chemotherapy alone. The combination also achieved its secondary endpoint of progression-free survival, recording 6.7 months versus 5.5 months with chemotherapy alone. Furthermore, the addition of Herceptin to chemotherapy improved the overall response rate by 12.8% to 47.3%, and reduced the risk of death in HER2-positive patients by 26% compared to those receiving chemotherapy alone.

Interestingly, high levels of HER2 expression were associated with greater clinical benefits with Herceptin. Herceptin binds to and inhibits HER2 signaling in tumors over-expressing the receptor and helps activate antibody-dependent cellular cytotoxicity to kill marked tumor cells. HER2 over-expression has been reported in 6%-35% of gastric cancers, which provided the perfect rationale for investigating Herceptin in this target population. According to Prof Cutsem, 22.1% of the 3,807 patients recruited in the ToGA trial were HER2-positive.

Advanced gastric cancer is incurable as it renders patients ineligible for surgery, resulting in a median survival of less than a year with the currently available chemotherapy agents. The impressive outcomes reported with Herceptin in the ToGA trial help set it apart from other established targeted agents such as Avastin (bevacizumab; Genentech/Roche/Chugai) and Tykerb (lapatinib; GlaxoSmithKline), which are also pursuing line extensions into gastric cancer. Based on these positive results, Roche is now seeking regulatory approval of Herceptin for first-line advanced gastric cancer. Prof Cutsem concluded that Herceptin represents a major therapeutic advancement for the treatment of late-stage gastric cancer, which has so far been associated with poor clinical outcomes. Datamonitor agrees that Herceptin is set to become the first targeted agent to be approved for advanced gastric cancer, where it will revolutionize disease management as it has done for HER2-positive breast cancer patients over the past 10 years.

The ASCO meeting also indicated that, in this era of targeted therapies, chemotherapy continues to flourish due to the synergies which it can provide with new treatments. For example, Dr Alfonso Duenas-Gonzalez presented encouraging evidence for Gemzar's (gemcitabine; Eli Lilly) synergistic effect with cisplatin, including promising outcomes in otherwise difficult-to-treat locally advanced cervical cancer. The results of an "ambitious" multicenter, randomized, Phase III trial showed that the addition of Gemzar to cisplatin and concurrent radiotherapy significantly improved progression free survival at three years for women with stage IIB to IVA cervical cancer.

In a post-presentation discussion, Dr Amit Oza agreed that the survival benefits seen in this trial were substantial given the persistent high unmet need for new therapies for cervical cancer. Indeed, the disease is the second-leading cause of cancer-related deaths in women. At a time when a multitude of targeted agents are being developed and used for a variety of oncology indications, the treatment of cervical cancer has remained stagnant. Conventional cisplatin and radiotherapy treatment has been considered the standard of care for over a decade. The results of this Phase III trial support the use of concurrent chemoradiation and adjuvant chemotherapy as the new standard of care. However, both Dr Duenas-Gonzalez and Dr Oza concluded that further studies are necessary to determine the optimal application of the new combination regimen in order to clearly define the benefits and toxicities of Gemzar when given as a component of chemoradiation or adjuvant chemotherapy.

Gemzar was also investigated in combination with cisplatin in the treatment of 204 patients with advanced/metastatic biliary tract cancer, in the trial ABC-02. The combination significantly improved median survival to 11.7 months versus 8.3 months for single agent Gemzar, without the addition of any significant toxicity. Biliary tract tumors represent rare forms of gastrointestinal cancers, for which surgery is the only current cure. In Japan, Gemzar has been approved for use in biliary tract cancer since July 2006.

Both the Phase III trials discussed demonstrate a survival benefit in difficult-to-treat indications using combined cytotoxic chemotherapy that includes Gemzar. As a result, Datamonitor believes that Eli Lilly is likely to be successful in expanding its use into these tumor types in addition to lung, breast, ovarian and pancreatic cancers for which Gemzar is already approved.

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