Cancer researcher Don Berry, PhD, from the University of Texas M.D. Anderson Cancer Center recently weighed in on the results taken from the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial fallout, which have generated controversy among the medical and pharmaceutical community.
The ALTTO study showed that when lapatinib (Tykerb/Tyverb) is added to the standard form of trastuzumab (also known as Herceptin) therapy following surgery, it does not appear to improve survival rates in women with early HER2-positive breast cancer.
The data was recently presented at the American Society of Clinical Oncology’s (ASCO) annual meeting, leaving many breast cancer researchers baffled, as reported by Kate Johnson at MedScape Medical News in her article, “ALTTO Fallout Focuses Debate on the Meaning of pCR.”
Researchers believed that combining both lapatinib and trastuzumab would lead to an improvement in patient survival — a hypothesis that was previously suggested by the neoadjuvant NeoALTTO trial, whereby this combination therapy would lead to a shrinking of tumors prior to surgery. This effect, which is known as pathologic complete response (pCR) was thought to be directly linked with extended survival in cancer patients.
Since ALTTO failed to prove this hypothesis, breast cancer drug development has reached a halt. Even though the US Food and Drug Administration (FDA) has remained silent so far, it was previously convinced of pCR’s prognostic value, releasing new guidance in 2012 stating that drugs that can cause pCR could get approved faster for use in the clinic, saving a lot of time and money for clinical trial research.
The results presented at the ASCO meeting have generated quite a controversy, with prominent researchers in the field starting to express their different opinions.
Laura Esserman, MD, a noted breast cancer researcher and surgeon who serves as director of the University of California, San Francisco’s Carol Franc Buck Breast Care Center, and who also served as co-principal investigator for the I-SPY 2 trial, a study testing the drugs veliparib (AbbVie Inc.) and neratinib (Puma Biotechnology) for triple negative breast cancer patients, said in the MedScape piece, “pCR is absolutely a good predictor of outcome. Actions speak louder than words, and there’s no withdrawal of the FDA’s draft guidance.”
The I-SPY trial, which BioNews Texas covered previously, aimed to accelerate drug development, defining pCR as its primary end point, and generating results showing that pCR can be predictive of survival. However, some skeptics still exist regarding this trial. Kathy Miller, MD, associate professor of medical oncology at the Indiana University School of Medicine in Indianapolis, said in the MedScape article, “pCR has always been a very imperfect surrogate. It is not a good surrogate for survival at all in patients with estrogen-receptor-positive disease, and it is a better though still very much imperfect surrogate for those with triple-negative disease or HER2-positive/estrogen-receptor-negative disease.”
However, both Dr. Esserman and MD Anderson researcher Dr. Don Berry, who was also involved in the I-SPY trial, are concerned with the interpretation that ALTTO failed to confirm the NeoALTTO pCR findings, disagreeing with the conclusions resultant from the ASCO meeting controversy. Dr. Berry said that statistically both trials are very consistent. “The arguments coming out of ASCO about the relevance of neoadjuvant end points are based on ALTTO not reproducing NeoALTTO. These arguments are based on a misinterpretation of statistical significance or lack thereof. Namely, NeoALTTO was ‘statistically positive’ for pCR, while ALTTO was ‘statistically negative’ for event-free survival. Statistical significance does not imply truth, and lack of statistical significance does not imply falsity,” he added, as quoted in the MedScape article.
Both trials appear to reveal some inconsistencies that are worth noting, proving it difficult to infer the results from one trial to the other. According to Dr. Esserman, “I don’t think the ALTTO story should be the one to kill pCR in terms of accelerated development. This makes me feel even more strongly that this is an important model to test. I honestly cannot understand why we would abandon this process. Why would we want to go back to a method that guarantees we have a 15-year turnaround for drug approval? There is no reason for us not to continue down this path. My personal belief is that we should be driving to compress the timeline, that we owe it to our patients and to science, that there is absolutely no downside to moving forward, and that there is no indication at this time, certainly from this trial, that we should abandon everything.”
Furthermore, the differences in estrogen-receptor status, node status, and duration and sequence of therapy can all account for the unanticipated ALTTO results.
Dr. Miller riposted, stating that the potential implications the ALLTO results will have for relying on pCR as a surrogate will probably result in a deleterious effect on the I-SPY trial. She believes that the potential downsides of accelerated approval need to be discussed, since this can generate false positive results, leading to bigger consequences for both patients and researchers.
Both Dr. Miller and Dr. Esserman agree that the ALTTO fallout generated confusion, however Dr. Esserman is confident that the I-SPY trial and its pCR endpoint are not compromised.
“There’s not going to be a big surprise in the final FDA guidance. I-SPY investigators are still totally on board, the FDA is totally on board. I’ve been in touch with them, and there isn’t anything here that I believe has changed their stance. This path forward will dramatically change the time it takes to get access to drugs for our patients. We absolutely have to run this experiment. We cannot abandon it.”