• 5/13/2005
  • Orlando, FL
  • Lynne Peterson
  • MedPage Today (www.medpagetoday.com)

The most important meeting of the year devoted to the frustrating but relentless pursuit of better treatments of cancer begins tomorrow.

It is a critical meeting for cancer doctors to hear the latest approaches to helping their patients live extra weeks, months, or even years. The oncologists will be looking to see how to use drugs to bypass refractory disease and how to outsmart tumors that have developed drug resistance.

They will be listening to reports on whether drugs should be given in the adjuvant setting, neoadjuvant setting, or not at all in conjunction with surgery. They will hear reports on chemoradiation plus surgery, or radiation alone, or surgery alone. The variety of reports will be dizzying.

For the pharmaceutical industry, a report that a new drug has an effect against a major cancer can add hundreds of millions of dollars, or more, to their fortunes. It doesn’t have to be a big advance for a new drug, or a new way to use an older drug. In the cancer world, it’s extremely rare to see a home run. Singles are rare enough.

As always there will be a mountain of data presented during the annual meeting of the American Society of Clinical Oncology, known far and wide as ASCO. But the really “big” findings may sound familiar because the pharmaceutical companies have already released broad-brush accounts — minus key details — of some of the most anticipated reports. But the devil could be in the details, which is what most in the cancer community will be dissecting beginning with tomorrow’s opening sessions.

The data most likely to change the way oncologists treat cancer patients will be news about expanded uses for already-approved drugs, particularly Millennium’s Velcade (bortezomib) and three agents from Genentech — Tarceva (erlotinib), Avastin (bevacizumab), and Herceptin (trastuzumab) — and combinations of those agents.

ASCO President-elect David H. Johnson, M.D., who is deputy director of the Vanderbilt-Ingram Cancer Center, described what he sees as the big stories out of ASCO this year. “Avastin will change how we treat non-small cell lung cancer, and Herceptin may well become standard-of-care as adjuvant therapy for breast cancers that are HER-2/neu positive,” he said. “These are the big treatment stories.” There is also a report on changing one’s diet to reduce the chances of a recurrence of breast cancer.

Herceptin is already FDA-approved to treat metastatic breast cancer, and data from three late Phase III trials that will be presented here may move it into the early, adjuvant setting. Three of these trials were recently stopped early because they showed substantial improvement in progression-free survival. Oncologists will be looking at magnitude and sustainability of the survival benefit as well as safety data, especially cardiotoxicity, in these trials.

Genentech is hoping to expand the use of Tarceva, a once-a-day oral small molecule that has captured the epidermal growth factor receptor (EGFR) market for third-line treatment of non-small-cell lung cancer (NSCLC) because it showed a survival benefit while AstraZeneca’s Iressa (gefitinib) did not. Data presented at ASCO may suggest that Tarceva can be used in first- or second-line NSCLC, without respect to EGFR status, and may show that it works in a range of tumors and patient populations, including head and neck, breast, and pancreatic cancer (alone and in combination with Roche’s Xeloda [capecitabine]).

The Avastin take-away message from ASCO may be that this monoclonal antibody has the potential to be added to chemotherapy for most metastatic solid tumors, not just colorectal cancer but also renal cell, hepatic, breast, head and neck cancer, and more. In colorectal cancer, data from an Avastin single-agent study could open the door for longer use as monotherapy, and the data in non-Hodgkin’s lymphoma could expand use outside solid tumors. The critical questions will be safety, especially neuropathy and the risk of arterial thromboembolic events (stroke, heart attack, angina), and whether there are strategies that will reduce these risks, subgroup response, and dosing.

Imclone’s late-to-the-game EGFR inhibitor, Erbitux (cetuximab), has been slowly gaining popularity in colorectal cancer, and data presented here could move it to use in earlier disease and further broaden its market. It could even challenge Avastin if the response rate meets or exceeds that for Avastin in first- or second-line colorectal cancer, though that was considered unlikely. Data also will be presented on several potential new uses for Erbitux in gynecologic malignancies, head and neck cancer, and recurrent NSCLC.

New data on Velcade in lung cancer, mantle-cell lymphoma, and front-line multiple myeloma have the potential to expand use of this proteasome inhibitor beyond refractory multiple myeloma. However, the neuropathy and myelosuppression side effects plus the high cost may not make this a first choice over existing agents.

Combination therapy with these expensive new therapies also is likely to get a boost from the presentations at ASCO. Phase II data on Tarceva plus Avastin, both in non-small-cell lung cancer and in renal cell carcinoma, are expected to show the combination is additive, if not synergistic. Another Phase II study aims to show that Avastin is synergistic with Erbitux in colorectal cancer. Triplet therapy with Avastin plus Tarceva plus Gleevec (imatinib) is another option being explored in renal cell carcinoma. Early (Phase I) data on the combination of Tarceva and Herceptin in advanced solid tumors, particularly breast cancer, looks promising, too. However, other combination therapies in the past have flopped after a strong beginning, and the price of two or more targeted agents may be prohibitive, at least for the near future.

Other data are likely to change the way standard therapies are used. An Eastern Cooperative Oncology Group study (ECOG-2197) will advise whether adjuvant treatment with Taxotere (docetaxel) plus Adriamycin (doxorubicin) is as effective in early-stage breast cancer as the standard therapy of Adriamycin and Cytoxan (cyclophosphamide). Another study will determine whether Femara (letrozole), an aromatase inhibitor, is more effective in preventing breast cancer recurrence than tamoxifen.

Incremental new data could boost the use of other approved drugs, including Tarceva and Gemzar (gemcitabine) in pancreatic cancer, and Rituxan (rituximab) for maintenance therapy in non-Hodgkin’s lymphoma. There will also be data that could lead to expanded uses of existing drugs for cancer prevention, such as statins for breast cancer, and selective estrogen receptor modulators (SERMs) — Acopodene (toremifen) for prostate cancer and Evista (raloxifene) for endometrial cancer.

Several promising investigational drugs will have positive data at ASCO, including sorafenib (BAY-43-9006), sutent (SU-11248), and lapatanib.

In renal cancer, Bayer/Onyx announced positive Phase III interim results for sorafenib in early April, but ASCO will be the first chance to see the details. Sutent is not far behind, and if the Phase II data are good, Pfizer may file on that data rather than waiting for Phase III data, or oncologists may opt to use it off-label in renal cell carcinoma. Sutent is in later stage development in gastrointestinal stromal tumors (GIST), now dominated by Gleevec, and that Phase III data also will be released at ASCO. Pfizer, which announced in February that the sutent GIST trial was stopped because it met the primary endpoint of improvement in time-to-progression, is expected to submit sutent to the FDA before the end of 2005. In any event, clinicians will be looking to compare the two agents on progression-free survival, response rate, efficacy, and toxicity.

Finding effective agents in metastatic melanoma has proven difficult, so expectations are low for sorafenib, Vitaxin, and Xyotax (polyglutamate paclitaxel, CT-2103). The sorafenib data are from an early Phase I trial, and the Vitaxin data come from a Phase II open-label study. Response rates of about 15% would probably be needed to warrant continued development.

Not all the news at ASCO will be positive.

The CONFIRM-1 trial of Novartis’s vatalanib (PTK-787), a possible oral competitor to Avastin, missed its primary endpoint of time-to-progression in metastatic colorectal cancer, but Novartis officials have said they are not giving up on vatalanib. There is likely to be significant interest in both time to progression and the co-primary endpoint of progression-free-survival, which the core lab said wasn’t met but an investigator assessment found did meet statistical significance.

The failure of the SPIRIT-1 and SPIRIT-II trials in NSCLC has Ligand searching for a way to expand Targretin (bexarotene) outside of cutaneous T-cell lymphoma. Likewise, the disappointing results in NSCLC of Cell Therapeutics’ CT-2106 (polyglutamate camptothecin) in the Phase II STELLAR-3 trial, will be examined to see whether any hopeful spots can be found.

Not all the news at ASCO will be about new and existing drugs.

Studies also should shed new light on the issues facing cancer survivors, genetic studies to help identify who will respond to cancer therapy, disparities in care, and the needs of cancer survivors, especially survivors of childhood cancers.