By Jay Grisolano, PhD and Stephanie Ritz, PhD
Approximately a quarter of breast cancer patients are classified as HER2-positive, according to Kantar Health’s 2016 Treatment Architecture data. 1 Effective targeted agents for the HER2 receptor, such as Herceptin (trastuzumab; Roche) and Perjeta (pertuzumab; Roche), have been developed for this particular patient segment and have greatly improved clinical outcomes for these patients. Despite these major advances, the need for improved early stage treatments still exists to keep disease from reaching an incurable stage. Currently, up to one in three early stage HER2+ patients treated with Herceptin in combination with chemotherapy eventually recur.2 In an effort to address this unmet need, Roche is conducting the Phase 3 APHINITY trial (NCT01358877) evaluating the combination of Herceptin, Perjeta, and chemotherapy in the adjuvant setting, hoping to improve upon these outcomes.
The triplet combination of Herceptin, Perjeta, and chemotherapy was initially approved in the HER2+ metastatic setting for first-line patients based on data from the Phase III CLEOPATRA trial, showing addition of Herceptin and Perjeta to chemotherapy improved median progression-free survival (PFS) and median overall survival (OS).3 In addition, the triplet has already demonstrated efficacy in early stage disease. The Phase II NEOSPHERE study (NCT00545688) compared Herceptin plus docetaxel with or without Perjeta in the neoadjuvant setting. Results reported at ASCO 2015 and published in Lancet Oncology showed a significantly improved complete response without an increase in cardiotoxicity (Herceptin / docetaxel: pCR 21.5%; Herceptin / docetaxel / Perjeta: pCR 39.3%, p=0.0063). Additionally, the risk of disease progression or recurrence was reduced by 31% and 40%.4 Based on these data, the triplet neoadjuvant regimen was granted approval in September 2013.
Now Roche is pushing to move their triplet combination into the adjuvant setting with APHINITY, results of which were presented today at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO).5 APHINITY is an international, double-blind, placebo-controlled Phase III trial evaluating the efficacy of Herceptin plus chemotherapy with or without Perjeta in the adjuvant setting. The study enrolled 4,805 patients of lymph-node-positive and -negative status with confirmed HER2 positivity, as defined by IHC3+ or FISH-/CISH-positive. Patients received 6 to 8 cycles of chemotherapy with Herceptin (8mg/kg) and Perjeta (840 mg)/placebo, followed by Herceptin (6 mg/kg) and Perjeta (420 mg)/placebo alone every 3 weeks for one year (52 weeks) of treatment. At the time of presentation, the primary endpoint of invasive disease-free survival (IDFS) in the overall population was 92.3% in the triplet arm versus 90.6% seen in the control arm (p=0.045) at four years; however, subgroup analysis suggested that clinical benefit for IDFS appeared to be limited to node-positive and hormone receptor-negative cohorts. The disease-free interval and recurrence-free interval was modestly improved (DFI: 93.4% v. 92.3%, p=0.033; RFI: 95.2% vs. 94.3%, p=0.043); however, the addition of Perjeta did not improve the distant recurrence-free interval. No difference was noted in median overall survival at first interim analysis (97.7% v. 97.7%, p=0.467), but only one-quarter of data points needed for final analysis had been collected.
The most common Grade 3/4 adverse events associated with the triplet arm included neutropenia in 16.3% of patients (versus 15.7% in the control arm), febrile neutropenia in 12.1% of patients (versus 11.1% in the control arm, anemia in 6.9% of patients (versus 4.7% in the control arm), and diarrhea in 9.8% of patients (versus 3.7% in the control arm), which was predominately observed during the administration of chemotherapy. Cardiac toxicity was low and similar between the two arms.
Based on these data, it will be interesting to see how physicians adopt the triplet regimen in the adjuvant setting if it gains accelerated approval. Physician attendees vocalized great concerns during today’s session regarding the financial burden of adding Perjeta for a modest 1.7% IDFS benefit, despite its favorable tolerability profile. It may be essential for Roche to find specific subsets of patients who benefit most from the triplet in order for physicians to seriously consider integrating the addition of Pejeta into their practice. Another concern is whether Perjeta retreatment of a patient who recurs with metastatic disease will still be effective. It was mentioned that trials are being initiated to evaluate retreatment with Perjeta. Given the modest efficacy of APHINITY and the current absence of data supporting retreatment with the triplet beyond progression, physicians may to choose to save Perjeta until the metastatic setting. These issues may make it difficult to compete with Puma’s HER2 tyrosine kinase inhibitor, neratinib, which already has a PDUFA date set for July. Data supporting Puma’s application for approval is based on the Phase III ExteNET (NCT02400476) study, which showed a 2% benefit in 2-year DFS (2-year rate: 93.9% vs. 91.6%, p=0.0009) with a relatively well-tolerated toxicity profile.6 Subgroup analysis showed that neratinib may be more effective in ER-positive patients, which could help Puma find its niche in this space should neratinib receive approval.
Nevertheless, APHINITY did meet its primary endpoint showing that addition of Perjeta to Herceptin and chemotherapy as adjuvant treatment achieved a statistically significant improvement in IDFS. These data suggest that the triplet may become an option for adjuvant treatment of HER2+ early breast cancer.
By Liseth Parra, Ph.D., and Stephanie Hawthorne, Ph.D.
A very exciting therapeutic area that has been constantly highlighted throughout ASCO this year is the enormous potential for targeting genomic instability. While genomic stability is a major force of tumor growth, it provides a vulnerable point of tumorigenesis that can be used as an actionable target in clinical oncology. BRCA1 and BRCA2 are responsible for activating DNA damage response pathways as a result of DNA double-strand breaks (DSB) and thus play an important role in maintaining the genetic stability of cells.
Hereditary (germline) mutations in one copy of either the BRCA1 or BRCA2 gene (gBRCA1/2) are associated with a high risk of developing primarily breast and ovarian cancer and represent one of the greatest unmet needs in gynecologic cancers. These mutations account for about 5% to 10% of all breast cancers and about 15% of all ovarian cancers1 and are particularly vulnerable to poly(ADP-ribose) polymerase (PARP) inhibition. PARP proteins normally function in the repair of DSB, and it’s presumed that their inhibition leads to the breakdown of the DNA machinery involved in DSB repair that cannot take place in BRCA1/2 deficient cells, a concept referred to as synthetic lethality.
Within the past two years, three PARP inhibitors gained regulatory approval for the treatment of advanced ovarian cancer – Lynparza® (olaparib, AstraZeneca), Rubraca® (rucaparib, Clovis Oncology), and Zejula™ (niraparib, Tesaro). Additionally, four PARP inhibitors – Lynparza, talazoparib (Pfizer / Medivation), veliparib (ABT-888, AbbVie), and Zejula – are in Phase III development for locally advanced or metastatic BRCA1/2 mutated breast cancer, starting a race to see which agent will be first to market in this indication.
AstraZeneca, as an output of its 2005 acquisition of the British biotechnology company KuDOS, became the first pharmaceutical company to launch a PARP inhibitor, with Lynparza obtaining accelerated approved as a monotherapy for the treatment of gBRCA ovarian cancer patients previously treated with three or more lines of chemotherapy. Following this initial launch, AstraZeneca has an extensive life-cycle management development plan in-place for Lynparza, with its eyes on breast cancer as the next indication for approval.
In the Plenary session at the 2017 ASCO conference, the first randomized results to support its development in breast cancer were presented1,2. The Phase III OLYMPIAD trial (NCT02000622) evaluated Lynparza in comparison to “physician’s choice” chemotherapy (capecitabine, vinorelbine, eribulin) in 302 metastatic HER2- breast cancer patients with deleterious or suspected gBRCA mutations.
Patients could have had up to two prior lines of chemotherapy and must have received prior anthracycline and taxane, and hormone receptor-positive patients must have received at least one prior line of hormone therapy unless considered unsuitable; ultimately, one-third of enrolled patients were treated on-study as first-line therapy for metastatic disease, one-quarter as third-line, and the remainder as second-line.
Late breaking results for this trial presented at ASCO demonstrated for the first time positive data for a PARP inhibitor in metastatic breast cancer with a statistically-significant improvement in progression-free survival (PFS) compared to standard chemotherapy and a meaningful improvement in health-related quality of life (HRQoL) in these patients.
The data showed a statistically significant PFS gain of nearly 3 months in patients treated with Lynparza (300 mg BID; n=205) versus chemotherapy (n=97) (7.0 vs 4.2 months, respectively; HR 0.58; p=0.0009). Although immature, overall survival (OS) was not statistically different between the two arms (19.3 versus 19.6 months, HR 0.90; p=0.5665). The ORR in the two arms was 60% versus 29%, respectively, with more complete responses in patients treated with Lynparza (9%) versus chemotherapy (2%). Although exploratory, data suggest similar level of benefit regardless of patient’s prior exposure to platinum or other chemotherapy, but suggest greater benefit in patients with triple-negative breast cancer (PFS HR 0.43) than in patients with hormone receptor-positive disease (PFS HR 0.82).
Fewer patients in the Lynparza arm than in the chemotherapy arm experienced Grade 3/4 adverse events (AE; 36.6% vs. 50.5%) and slightly fewer AE-related treatment discontinuations (4.9% vs. 7.7%). The most common Grade 3/4 adverse events in the Lynparza and chemotherapy arms were anemia (16% vs. 4%) and neutropenia (9% vs. 26%). As a secondary endpoint, the results showed that Lynparza led to a modest but clinically meaningful improvement in HRQOL compared to chemotherapy (estimated difference in EORTC QLQ-C30 global HRQOL score of 7.5 points, p=0.0035) and significantly longer time to deterioration of HRQOL (median not reached vs. 15.3 months; HR 0.44, p=0.0043).
These results represent the first positive Phase III trial for a PARP inhibitor in breast cancer and the discussant, Dr. Allison Kurian, had an overall positive outlook stating that these results” are practice-changing.” However, the magnitude of the benefit (3 months difference) and lack of OS benefit could raise questions by others in the field about the clinical meaningfulness of these results.
It is encouraging that the incidence of adverse events was lower, fewer treatment discontinuations were needed, and HRQOL was improved with Lynparza, but the magnitude of each of these improvements seems to run on the edge of meaningful from the a clinical perspective. When the clinical benefits run along that edge, commercial considerations have a greater likelihood of taking hold, and some physicians (and payers) may question whether the benefit with Lynparza compared to generic chemotherapy justifies the costs. Despite these concerns, Lynparza stands a good chance of gaining regulatory approval, so these debates may ultimately play out in the clinic and everyday practice.
While it may launch as a monotherapy, ultimately the greater movement forward with PARP inhibitors lies in alternative development strategies. Correlative biomarkers for PARP inhibition (beyond gBRCA1/2) may help to further identify patients that will benefit the most from Lynparza. Additionally, the double-hit approach of single-agent PARP inhibitors in gBRCA mutated disease may not be robust enough, and we could ultimately find more effective strategies with a targeted combination approach – this includes combinations with chemotherapy or radiotherapy (which can induce DSBs)or with other mechanisms of action.
The closest drug taking this approach is veliparib, which is being studied in the Phase III BROCADE 3 trial (NCT02163694), which is enrolling HER2- breast cancer patients harboring deleterious BRCA1/2 or gBRCA1/2 mutations with less than two lines of prior therapy, who will be randomized to treatment with carboplatin and paclitaxel in combination with veliparib or placebo. Other PARP inhibitors in development in breast cancer are being developed as monotherapies – talazoparib in the Phase III EMBRACA trial (NCT01945775 and Zejula in the Phase III BRAVO trial (NCT01905592). The OlympiAD results, Lynparza is now officially ahead of the competition and could emerge as a potential agent of change in gBRCA breast cancer management, creating a new standard of care for the gBRCA1/2-mutated patient population. With so many competitors hot on its heels, it will be critical for Lynparza to get a solid push off of the starting block in order to put as much distance between itself and the others in this Olympic race in the breast cancer market.
By Megan Epperson, PhD, and Arnold DuBell, PhD, MBA
For HR+/HER2- advanced breast cancer patients, endocrine therapy has proved to be an effective and well-tolerated treatment option. In order to delay the initiation of more cytotoxic therapies, physicians will typically utilize hormone therapy as long as possible in these patients, although the majority will become resistant to hormone therapy. In recent years, pairing hormone therapy with targeted therapies has become a popular strategy. This strategy began in 2011 with the data from BOLERO 2, which found that addition of Afinitor® (everolimus, Novartis) to exemestane could help re-sensitize patients to hormone therapy regimens1. Even more recently, physicians are combining hormone therapy with cell cycle inhibitors targeting the cyclin-dependent kinases 4 and 6 (CDK4/6). First to lay claim to this concept was Ibrance® (palbociclib, Pfizer), which was first approved in 2015 by the U.S. FDA as first-line therapy in combination with letrozole (later loosened to include all aromatase inhibitors,) based on the PALOMA-1 trial2. Further, after the results of the PALOMA-2, and -3 trials were presented, the FDA and the EMA approved Ibrance as first-line therapy in combination with aromatase inhibitor or as a second-line option in combination with either an aromatase inhibitor or Faslodex® (fulvestrant, AstraZeneca)3,4. There are now two more players in addition to Ibrance targeting CDK4/6 for inhibition in breast cancer: Kisqali® (ribociclib, Novartis), and abemaciclib (Eli Lilly and Company). Kisqali was approved by the FDA in March 2017 for use in the first-line setting in combination with an aromatase inhibitor based on positive data from MONALEESA-25. As targeting of this pathway has proven to yield effective results in breast cancer, many trials have been initiated utilizing this class of inhibitors in breast cancer. Currently, there are 60 active trials involving these three inhibitors in breast cancer (Kantar Health’s CancerLandscapeTM, accessed June 2, 2017). Lilly is also interested in this space for their CDK4/6 inhibitor abemaciclib, having initiated two global Phase III trials (MONARCH 2 and MONARCH 3) in HR+/HER2- metastatic breast cancer.
Top-line results were presented from MONARCH 2 today at the American Society for Clinical Oncology (ASCO) annual meeting. This trial randomized 669 patients to abemaciclib (150 mg or 200 mg, po, BID) in combination with Faslodex (150 mg or 200 mg, po, BID) or placebo plus Faslodex in HR+/HER2- advanced breast cancer patients as either a first- or second-line treatment option6. Patients enrolled in MONARCH 2 were allowed to have progressed on neoadjuvant, adjuvant, or first-line endocrine therapy. Notably, MONARCH 2 differed from PALOMA 3 in that the use of prior chemotherapy was an exclusion criterion. The addition of abemaciclib significantly improved progression-free survival (PFS; 16.4 months versus 9.3 months, HR 0.553, p<0.0000001). MONARCH 2 also met its secondary endpoint of overall response rate (ORR in the intent-to-treat population; 35.2% versus 16.1%, p<0.001). Although not significant, the rate of complete responses was also improved with the addition of abemaciclib (3.5% versus 0%).
Toxicity may be an issue for abemaciclib. Of specific concern, the incidence of diarrhea was increased with abemaciclib (all grades, 86.4% versus 24.7%; Grade 3-4, 13.4% versus 0.4%). Due to discontinuations related to this adverse event, the dose of abemaciclib was reduced from 200 mg to 150 mg after enrollment of 178 patients. The discontinuation rate before the dose reduction was 24%, and post-reduction discontinuations dropped to 13%. The presenter noted in his summary, however, that diarrhea was manageable with use of loperamide. Other grade 3-4 toxicities of note included neutropenia (26.5% versus 1.7%), leucopenia (8.8% versus 0%) and anemia (7.2% versus 0.9%). As the trial met its PFS primary endpoint, Lilly announced that it intends to file for approval of abemaciclib in Q3 2017 (Press Release, March 20, 2017).
With Ibrance’s 2015 approval and the recent approval of Kisqali, abemaciclib will be third-to-market in the HR+/HER2- advanced breast cancer setting. All three inhibitors appear to provide benefit to patients as all showed significant improvements in PFS. While both Ibrance and Kisqali have similar toxicity profiles, abemaciclib alone appeared to struggle with higher incidences of diarrhea. While it is not completely clear why abemaciclib differs in its toxicity profile in this way, it may be related to the fact that abemaciclib is more potent against CDK4/cyclin D1 than CDK6/cyclin D3 in enzymatic assays; the reverse is true for Ibrance and Kisqali. The dosing strategy for abemaciclib also differs from Ibrance and Kisqali in that it is administered via continuous dosing, while the other two inhibitors are administered for 21 days, with a 7 day treatment holiday per cycle. Given the hurdles, these data are only “semi-sweet”: good enough for regulatory approval, but the toxicities seen in MONARCH 2, and abemaciclib’s eventual third-to-market introduction might cause physicians to question when to offer the agent.