Perjeta (pertuzumab; Genentech/Roche/Chugai) is poised for a label expansion into the early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer setting after a positive readout from the Phase III APHINITY trial (ClinicalTrials.gov identifier: NCT01358877). In the trial, the combination of Perjeta, Herceptin (trastuzumab; Roche/Chugai), and chemotherapy showed a statistically significant improvement in invasive disease-free survival (iDFS) over Herceptin and chemotherapy alone for the adjuvant treatment of early-stage HER2+ breast cancer patients (Roche press release, 2017). This significant improvement in survival will likely mean the Perjeta/Herceptin/chemotherapy combination will be considered the new standard of care for early-stage HER2+ breast cancer patients receiving surgery.
However, full efficacy and tolerability results, including the exact iDFS rates, are needed to fully determine the Perjeta/Herceptin/chemotherapy combination’s potential, as its survival advantage over Herceptin plus chemotherapy will have to be significant to justify the overall cost of the regimen. The Perjeta/Herceptin combination could cost up to $160,000 annually, excluding the cost of chemotherapies, and could be a large hurdle for regulatory bodies when considering reimbursement of the regimen. In 2016, this high price resulted in the UK’s National Institute for Health and Care Excellence (NICE) rejecting reimbursement of Perjeta in combination with Herceptin for the neoadjuvant setting. Roche eventually offered a confidential discount on Perjeta, prompting NICE to reverse its decision (NICE press release, 2016a; NICE press release, 2016b).
Nonetheless, a label expansion into the early-stage adjuvant setting for Perjeta would be an important step for Roche as it tries to maintain its dominance of the HER2+ breast cancer market. The company will increasingly rely on uptake of Perjeta and its HER2-targeted antibody-drug conjugate, Kadcyla (ado-trastuzumab emtansine; ImmunoGen/Roche/Chugai), to offset the eventual decline in Herceptin’s sales due to biosimilar competition. The anticipated growth of Perjeta’s and Kadcyla’s sales is largely due to potential label expansions into early-stage breast cancer, a segment containing a large number of patients. In addition to the Perjeta/Herceptin/chemotherapy combination, Roche is also investigating Kadcyla in the early-stage adjuvant setting as a monotherapy in the Phase III KATHERINE trial (ClinicalTrials.gov identifier: NCT01772472). Furthermore, Perjeta and Kadcyla are being investigated as a combination in the early-stage adjuvant setting in the Phase III KAITLIN trial (ClinicalTrials.gov identifier: NCT01966471).
In contrast, results of the APHINITY trial likely spell bad news for Puma Biotechnology and its pan-HER inhibitor, neratinib. In 2016, Puma Biotechnology submitted for regulatory approval of neratinib for the extended adjuvant treatment of early-stage HER2+ breast cancer patients who have received prior adjuvant treatment with Herceptin. However, uptake of the Perjeta/Herceptin/chemotherapy combination would reduce neratinib’s eligible patient population as the drug has not been studied in patients who have received prior treatment with this particular combination. This further restricts neratinib’s potential, which was already somewhat confined by its limited efficacy and significant tolerability concerns. According to the five-year interim results of the Phase III ExteNET trial, neratinib improved disease-free survival by only 2.5% over placebo in the intent-to-treat population. Neratinib treatment was also associated with a 38% increase in the rates of high-grade diarrhea (Chan et al., 2016; Puma Biotechnology press release, 2016).
Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, et al. (2016) Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology, 17, 367–77.
NICE press release (2016a) Long-term benefits of breast cancer drug pertuzumab too uncertain says NICE in draft guidance. Available from: https://www.nice.org.uk/news/press-and-media/long-term-benefits-of-breast-cancer-drug-pertuzumab-too-uncertain-says-nice-in-draft-guidance [Accessed 2 March 2017].
NICE press release (2016b) Price discount helps give green light for breast cancer drug pertuzumab. Available from: https://www.nice.org.uk/news/article/price-discount-helps-give-green-light-for-breast-cancer-drug-pertuzumab [Accessed 2 March 2017].
Puma Biotechnology press release (2016) Puma Biotechnology Announces Interim 5-Year Disease Free Survival Data from Phase III Trial of PB272 (Neratinib) in Extended Adjuvant HER2-Positive Early Stage Breast Cancer (ExteNET Trial). Available from: http://www.pumabiotechnology.com/pr20160721_2.html [Accessed 2 March 2017].
Roche press release (2017) Phase III APHINITY study shows Roche’s Perjeta® regimen helped people with an aggressive type of early breast cancer live longer without their disease returning compared to Herceptin® and chemotherapy. Available from: http://www.roche.com/media/store/releases/med-cor-2017-03-02.htm?utm_source=360Works%20CloudMail&utm_medium=email&utm_campaign=11959 [Accessed 2 March 2017].