The Forward March of Regress
The Annual Meeting of the American Society of Clinical Oncology (ASCO) is one of the largest (if not the largest) cancer meetings in the world, and certainly within the United States. Practicing oncologists, nurses, physician scientists, research scientists, and thousands of pharmaceutical and biotechnology professionals, to say nothing of the myriad of patient support and advocacy experts, descend each year on Chicago the first weekend in June to network, recruit partners and allies, and of course to present the results of clinical trials both large and small.
The expectation within the American media, as well as within the culture it serves, is that ASCO should herald the announcement of some Grand New Development in cancer therapeutics, some kind of breakthrough treatment taking advantage of the bleeding edge of scientific and translational research to completely change the paradigm of care for some (or all) cancer patients. And while this does happen from time to time (such as with Herceptin or Gleevec), the advance of cancer care usually doesn’t follow this pattern. More often, new investigational agents are shown to make only incremental gains against the standard of care, subtly shifting the balance of the therapeutic index for patients. And sometimes new research shows that impressive new advances can be made with old drugs.
Take for example, the report on the Eastern Cooperative Group (ECOG) trial E3805 (aka “CHAARTED”), which compared androgen deprivation therapy (ADT) with or without the drug Taxotere in men with metastatic hormone-sensitive prostate cancer. In this trial, Dr. Christopher Sweeney explained that Taxotere, which had been approved in 2004 for use in metastatic prostate cancer (but only in men whose disease was no longer responsive to hormone therapy) had been shown to confer a two-month increase in overall survival. The hypothesis of this trial, however, was that Taxotere would be more effective at prolonging overall survival if administered before the metastatic disease became refractory to hormone therapy. It turned out that their hypothesis was right, as the addition of Taxotere to ADT resulted in an increase of nearly 14 months to median overall survival for the entire patient population, and an increase of 17 months for patients with high volume disease. Thus, a substantial gain in survival was achieved not by developing either new drugs for new targets, or even new drugs for old targets, but simply by using old drugs for old targets in a new way.
And sometimes new advances can’t be made with new drugs either. The first report of the Phase 3 collaboration between the Breast International Group and the Alliance for Clinical Trials in Oncology (previously known as the North Central Cancer Treatment Group), BIG-2-06/N063D (also known as “ALTTO”), was also reported at this year’s ASCO meeting. Dr. Martine Piccart-Gebhart discussed how she (along with co-PI Dr. Edith Perez) and many in the breast cancer community had been impressed by the improved survival outcomes associated with Herceptin use in the adjuvant setting for patients with early-stage HER2+ breast cancer, and designed the trial to determine if dual blockade of the HER2 receptor (using both Herceptin as well as the HER2-targeted tyrosine kinase inhibitor Tykerb) would provide any additional clinical advantage. The ALTTO trial was a massive undertaking, with over 8000 patients registered to four different treatment arms; I was present at the initial investigator’s meeting which kicked off the trial in 2007, and even then it seemed like a mind-boggling feat to accomplish. But accomplish they did, though it turned out to be a negative trial. In her presentation, Dr. Piccart-Gebhart explained that excluding the Tykerb monotherapy arm (which had been shut down in 2011 due to evidence it would not show non-inferiority to the Herceptin monotherapy arm), the three remaining arms were virtually indistinguishable in terms of disease-free survival and overall survival, and the Tykerb-containing arms demonstrated significantly higher incidence of adverse events, particularly with regard to diarrhea and rash.
The ALTTO results were a blow, not just to the study investigators and sponsors, but also to those who work in the field of breast oncology. In his commentary immediately following the ALTTO results, Dr. George Sledge (one of my favorite oncologists ever) expressed his frustration with the failure of the trial, not just because of its immediate ramifications, but because it signals a failure of the field of breast oncology to understand a key aspect of the disease, as well as to be able to extrapolate success in the neoadjuvant or metastatic settings to the adjuvant setting. It had been hoped that showing a benefit to pathologic complete response (pCR) in the neoadjuvant setting (which had been shown for the combination of Tykerb and Herceptin in the NeoALTTO trial) could serve as a reliable indicator of overall survival benefit in the adjuvant setting. Unfortunately, the experience with Herceptin in this regard now appears to be the exception, not the rule. Indeed, Dr. Sledge pointed out that the role of biologics as adjuvant therapy for multiple tumor types now appears to be largely futile.
But I don’t lose hope. Negative trial data may be disappointing, and they may be a psychological roadblock for research, but scientifically they are just as informative as positive data. Indeed, with the public presentation of ALTTO now all but completed (there will be some future updates that are unlikely to change the outcome), researchers can now move away from its answered question and explore other options. More molecular targets are ripe for investigation, such as PI3K, MET, and Hsp90. Researchers and pharmaceutical companies are hard at work on the bleeding edge of the oncological pipeline, and future ASCO meetings will display the fruits of their labor.