Roche's Perjeta, Herceptin regimen offers slight benefit in breast cancer trial

Roche's Genentech unit on Monday said the addition of Perjeta (pertuzumab) to Herceptin (trastuzumab) plus chemotherapy in the adjuvant setting significantly reduced the risk of breast cancer recurrence or death by 19 percent in patients with HER2-positive early breast cancer, compared to Herceptin and chemotherapy alone. Daniel Hayes, president of the American Society of Clinical Oncology (ASCO), commented that the outcome of the previously announced Phase III APHINITY trial "tells us the combination is better than the single regimen, but that the difference is small." 

The study, which was presented at the annual ASCO conference and simultaneously published in the NEJM, involved 4805 patients with node-positive or high-risk node-negative HER2-positive, operable early breast cancer. Patients were randomised to receive either Perjeta or placebo added to standard adjuvant chemotherapy plus one year of treatment with Herceptin. The primary efficacy endpoint is invasive disease-free survival (iDFS), defined as the time a patient lives without return of invasive breast cancer at any site or death from any cause after adjuvant treatment, while secondary endpoints include cardiac and overall safety, overall survival, DFS and health-related quality of life. 

Results from a primary analysis showed that at three years, 94.1 percent of patients given the Perjeta-based regimen did not have their breast cancer return, compared to 93.2 percent of patients treated with Herceptin and chemotherapy alone. Roche noted that the strongest effects of the combination were seen in patients with lymph node-positive or hormone receptor-negative disease. Specifically, 92 percent of patients with node-positive disease in the Perjeta arm did not experience recurrence of breast cancer at three years, versus 90.2 percent for placebo. The company reported that iDFS rates among patients in the hormone receptor-negative subgroup were 92.8 percent and 91.2 percent, respectively. Meanwhile, there was no significant difference between the treatment arms for patients whose disease had not spread to lymph nodes, the researchers said.

Serious side effects seen in the trial included heart failure or cardiac death in 0.7 percent of patients in the Perjeta group and 0.3 percent of the placebo group. Hayes suggested oncologists might refrain from using the new combination because Perjeta was also associated with severe diarrhoea in some cases, occurring at a rate of 9.8 percent in the Perjeta arm, compared with 3.7 percent for placebo. "I hope we'll be thoughtful about how we use Perjeta, without causing unnecessary diarrhoea, and without breaking the bank," he said. The US list price for a one-year course of the Perjeta/Herceptin regimen in the adjuvant setting is approximately $158 000, while Herceptin alone costs around $74 500.

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HSBC analysts suggested "the big question is whether the data are enough to convince clinicians that the standard of care in HER2-positive breast cancer is now the Herceptin and Perjeta combination." Sandra Horning, chief medical officer at Roche, said "we are looking at a setting where we are in the business of basically trying to cure patients… It's a very different setting for looking at absolute and relative differences than we might say in metastatic disease." Horning noted that at four years, the benefit of the Perjeta-based regimen seems to increase, and she predicted it will grow over the 10-year course of the APHINITY study.

In an accompanying NEJM editorial, Kathy Miller remarked "to be clear, APHINITY is a positive trial. To be equally clear, as compared to the results of [Perjeta] in the context of metastatic disease and neoadjuvant therapy, APHINITY is a disappointment." Miller stated Perjeta "will find a place in adjuvant therapy for patients with multiple involved lymph nodes or those who would accept substantial toxic effects for marginal benefit," but added that "the toxic effects [and cost of the regimen] are too great for too many to benefit too few." For further analysis, read ViewPoints: Roche's APHINITY data appears to fall below oncologist expectations.

The combination of Perjeta, Herceptin and chemotherapy is currently approved as a neoadjuvant treatment for patients with HER2-positive early breast cancer, including in the US and in Europe. Herceptin generated sales of around $7 billion for Roche last year, while revenue from Perjeta reached about $1.9 billion.

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