There are confirmed data from only 60% of the population. We have to watch this study and be careful about overinterpretation.
—Clifford Hudis, MD
Discussant Clifford Hudis, MD, Chief of Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York, highlighted neratinib’s benefits while also advocating caution in interpreting the results due to incomplete data, the serious side effect of diarrhea, and the potentially game-changing outcomes of the adjuvant trial testing pertuzumab (Perjeta).
In addition, Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, who discussed the study at the 2015 ASCO Annual Meeting, and Richard Gelber, PhD, Professor of Biostatistics at Harvard Medical School, Boston, put the ExteNET trial results into context with other studies in HER2-positive patients.
Noting that neratinib reduced the recurrence risk by 33%, Dr. Modi highlighted that ExteNET’s positive findings were discordant from the ALTTO and HERA trials. In HERA, overall survival was the same whether patients received 1 or 2 years of trastuzumab (Herceptin)—approximately 87% at 9 years. In ALTTO, the addition of lapatinib (Tykerb) to trastuzumab did not improve survival over trastuzumab alone (approximately 95% at 4 years).
Words of Caution
“There are confirmed HER2 data from only 60% of the population,” noted Dr. Hudis. “We have to watch this study and be careful about overinterpretation.”
Whether neratinib is “ready to be the new standard of care” is up for debate, concluded Dr. Modi. “On the one hand, I’d say yes, the absolute disease-free survival is real. These results are similar to what we saw with the 2-year data of the original adjuvant trastuzumab trials,” she pointed out. “But on the other hand, we have no overall survival data, and this is something we did have with the trastuzumab trials.”
What About Pertuzumab?
Dr. Modi also questioned the appropriate population for this drug. Pertuzumab is an option in the neoadjuvant setting for high-risk patients, and it is unknown whether neratinib’s benefit would persist in this group. In patients with low-risk disease, it could be difficult to justify the toxicity for a small potential benefit, she said.
“Preoperative studies for pertuzumab … showed a near doubling of the pathologic complete response rate,” added Dr. Hudis. “Accelerated approval that was granted to pertuzumab is just the beginning. If converted to full approval, it would raise a number of questions that would be challenges to the ExteNET trial results going forward.”
‘A Fatal Limitation’
Following the initial presentation at the ASCO Annual Meeting, Dr. Gelber took a more absolute stance. “I hypothesize that the short follow-up, which Dr. Chan acknowledged as a limitation of the study, is a fatal limitation,” he said. “I consider these results nonactionable. The early results of ALTTO showed an even larger advantage than we saw here. The curves separated early and came together later. Follow-up of ExteNET is much too short to take action.” ■
Disclosure: Drs. Hudis and Modi reported no potential conflicts of interest. Dr. Gelber is the senior independent statistician for the HERA, ALTTO, and APHINITY clinical trials, for which
his institution received research funds from Roche and GSK.