On June 2, 2018 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported interim clinical data from the LOXO-292 global Phase 1 LIBRETTO-001 (LOXO-292 Investigated to Block RET-altered Tumors) dose escalation trial (Press release, Loxo Oncology, JUN 2, 2018, View Source [SID1234527090]). LOXO-292 is an investigational, highly potent and selective RET inhibitor. These data are being presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract 102).

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"The LOXO-292 Phase 1 data are striking," said Alexander Drilon, M.D., clinical director in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and presenting author. "The activity we reported is impressive and I am thrilled to see this promising efficacy with limited adverse events, especially in this heavily pre-treated patient population of RET fusion cancers, including those with brain metastases, and RET mutated MTC."

"We are very excited to share the initial LOXO-292 clinical experience with the oncology community at ASCO (Free ASCO Whitepaper)," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "We have long believed that patients with RET fusion cancers and RET mutated MTC needed a purpose-built medicine tailored to their tumors. We hope that LOXO-292 continues to deliver on that premise. Thank you to the patients, investigators and clinical trial teams who made possible today’s presentation."

Trial Background

The LIBRETTO-001 Phase 1 trial contains a dose escalation phase and a dose expansion phase. The dose escalation phase follows a "3+3" design. LOXO-292 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in these cleared cohorts. Intra-patient dose escalation is also permitted as dose cohorts are cleared. The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by RECIST 1.1) and duration of response. The dose expansion phase is designed to further characterize the overall response rate, durability of response, and safety of LOXO-292 in predefined groups of patients with activating RET alterations.

Key Data Presented at ASCO (Free ASCO Whitepaper)

The data presented at ASCO (Free ASCO Whitepaper) were based on an April 2, 2018 data cut-off date. Eighty-two total patients had been enrolled to eight dose escalation cohorts: 20 mg QD (n=6), 20 mg BID (n=10), 40 mg BID (n=16), 60 mg BID (n=10), 80 mg BID (n=18), 120 mg BID (n=4), 160 mg BID (n=12) and 240 mg BID (n=6). RET alterations were identified by local laboratories either in tumor or plasma and included the following primary diagnoses:

38 patients with RET fusion-positive non-small cell lung cancer (NSCLC) (21 with prior MKI treatment, 17 without)
9 patients with RET fusion-positive thyroid cancer (8 with prior MKI treatment, 1 without)
2 patients with RET fusion-positive pancreatic cancer (1 with prior MKI treatment, 1 without)
29 patients with RET-mutated medullary thyroid cancer (MTC) (23 with prior MKI treatment, 6 without)
4 patients with no known activating RET alterations
In addition to many patients with prior MKI treatment, 46% of patients had received prior chemotherapy and 24% had received prior immunotherapy (47% of those with NSCLC).

Pharmacokinetic analyses during the dose escalation demonstrated dose-dependent increases in LOXO-292 exposure with increasing dose. Starting at the 40 mg BID dose and the 80 mg BID dose, respectively, LOXO-292 delivered sustained >IC90 RET fusion and >IC90 RET M918T-mutant target coverage, based on cell-based potencies.

The data presented at ASCO (Free ASCO Whitepaper), summarized below, are based on response assessments performed by each respective clinical trial site (local, investigator-assessed radiology).

1. Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2).
2. Excludes patients recently enrolled that remain on treatment, but have not had a first post-baseline response assessment.
3. Response status per RECIST 1.1. Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overall response rate: all RET fusion-positive (30/39, 25/34), RET fusion-positive NSCLC (23/30, 20/27), RET fusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18).
4. Excludes patients with unconfirmed CR/PR pending confirmation at time of data cut-off.
5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment.
6. Patients that discontinued treatment prior to a first post-baseline response assessment.

Anti-tumor activity was observed regardless of RET fusion partner (including KIF5B), RET mutation (including M918T and V804M gatekeeper mutations), and prior MKI treatment. Twelve patients with RET fusion cancers had central nervous system (CNS) metastases at enrollment and all remained on study without progression. Three of these patients had RECIST target lesions in the CNS, and all three exhibited intracranial partial responses. In patients with RET-mutant MTC, LOXO-292 treatment resulted in significant reductions in the serum tumor markers calcitonin and carcinoembryonic antigen (CEA).

As of the data cutoff, LOXO-292 demonstrated early evidence of durable activity, with 90% of RET fusion-positive cancer patients and 93% of RET-mutant MTC patients remaining on therapy. All responding patients across all tumor types remained on therapy. The longest responding patient on therapy was the first RET fusion-positive NSCLC patient enrolled, who had been on therapy for more than ten months as of the data cut-off date.

Most treatment-emergent adverse events were Grade 1 in severity. The treatment-emergent adverse events observed in ≥10% of patients, regardless of relationship to LOXO-292, were fatigue (12% Grade 1, 7% Grade 2, 0% ≥Grade 3), diarrhea (10% Grade 1, 6% Grade 2, 0% ≥Grade 3), constipation (13% Grade 1, 1% Grade 2, 0% ≥Grade 3), dry mouth (12% Grade 1, 0% ≥Grade 2), nausea (9% Grade 1, 4% Grade 2, 0% ≥Grade 3), and dyspnea (7% Grade 1, 2% Grade 2, 1% ≥Grade 3). Only two adverse events ≥Grade 3 were attributed to LOXO-292 (Grade 3 tumor lysis syndrome, Grade 3 increased ALT). An MTD had not been reached. At the 240 mg BID dose level, one dose limiting toxicity (DLT) was reported (aforementioned Grade 3 tumor lysis syndrome).

LOXO-292 also demonstrated robust reduction and clearance of RET alterations as detected in patients’ plasma cell free DNA (cfDNA). These data will be presented in a separate poster presentation on June 3, 2018.

LIBRETTO-001 Trial Update

The expansion cohorts of the LIBRETTO-001 trial are now open and enrolling at the 160 mg BID dose. This dose was selected for initial expansion based on its promising activity and tolerability profile. Additional dose exploration above 160 mg BID is ongoing and patients enrolled to the expansion cohorts may dose escalate should a higher dose be advanced.

About the ASCO (Free ASCO Whitepaper) Presentations

LOXO-292 data are being presented in two presentations at ASCO (Free ASCO Whitepaper):

"A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers." This abstract is being presented in an oral presentation by Dr. Alexander Drilon, Memorial Sloan Kettering Cancer Center, during a Clinical Science Symposium session entitled, "Tumor Genomics: Finding the Target, Hitting the Target" from 8:00 – 9:30AM CT on Saturday, June 2, 2018 (Abstract 102).
"Detection and clearance of RET variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292." This abstract is being presented as a poster by Dr. Geoff Oxnard, Dana Farber Cancer Institute, during the Lung Cancer—Non-Small Cell Metastatic poster session from 8:00 – 11:30AM CT on Sunday, June 3, 2018 (Abstract 9048).
The presentations will be available online at View Source at the time of their scheduled presentation at ASCO (Free ASCO Whitepaper).

Conference Call and Webcast Information
Loxo Oncology management will host a conference call and live webcast with slides and Q&A today at 4:00 p.m. CT to discuss the LOXO-292 data. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 3597058. A live webcast of the presentation will be available at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 30 days following the call.

On June 2, 2018 AstraZeneca and MedImmune, its global biologics research and development arm, reported that results from the Phase III (‘1053’) clinical trial (Abstract #7004) that evaluated moxetumomab pasudotox in 80 patients with relapsed or refractory hairy cell leukemia (HCL) who had received at least two prior lines of therapy.1 (Press release, AstraZeneca, JUN 2, 2018, View Source [SID1234527107])

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Moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin, showed a 75% objective response (OR) rate, a 41% complete response (CR) rate, and a 30% durable CR rate (primary endpoint). The majority of patients with a complete response had a durable response (73%; 24/33) and achieved a negative minimal residual disease (MRD) status (82%; 27/33). Findings from this pivotal trial were presented for the first time during an oral session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "Moxetumomab pasudotox is an investigational, first-in-class immunotoxin which we believe has the potential to advance outcomes for patients with relapsed or refractory hairy cell leukemia, a condition with a high unmet need. It is also the first agent to be submitted for regulatory review from our Antibody Drug Conjugates platform, and as such demonstrates our commitment to developing novel treatments for blood cancer."

Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, said: "Hairy cell leukemia is a rare, chronic blood cancer with no established standard of care for patients with relapsed or refractory disease following purine nucleoside analog therapy. With very few treatments available, there remains significant unmet medical need for people with relapsed or refractory disease. The response rates observed in this trial, and elimination of the residual leukemia cells that cause relapse in some patients, highlight the potential impact this potential new medicine could have on patients and the management of this disease."

Summary of key results from the Phase III ‘1053’ single arm, multicenter clinical trial in 80 patients with relapsed or refractory HCL (16.7 months median follow-up), as determined by a blinded independent central review:

The primary endpoint of the trial was durable CR, which is defined as CR with HR for >180 days. The median time to HR was 1 month. MRD refers to the small amounts of cancer cells that may remain after treatment.2 A high rate of negative MRD after therapy may further improve outcomes.3 The median duration of OR and median progression-free survival were not reached.

The most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%); 8% had infections and 3% had neutropenia deemed treatment-related. Three patient deaths occurred, none of which were determined to be treatment-related. Treatment-related AEs leading to discontinuation were hemolytic uremic syndrome (HUS; 4 [5%]), capillary leak syndrome (CLS; 2 [3%]), and increased blood creatinine (2 [3%]). Seven patients (9%) had CLS and seven (9%) had HUS; this includes four (5%) patients who had both CLS and HUS. CLS and HUS were manageable and reversible.

In April 2018, AstraZeneca announced that the US Food and Drug Administration (FDA) accepted the Biologics License Application (BLA) for moxetumomab pasudotox for the treatment of adult patients with HCL who have received at least two prior lines of therapy. The BLA is based on results from the Phase III ‘1053’ clinical trial. The FDA has granted Priority Review status with a Prescription Drug User Fee Act action date set for the third quarter of 2018.

NOTES TO EDITORS

About Moxetumomab Pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is an investigational anti-CD22 recombinant immunotoxin and a potential new medicine with the opportunity to be a first-in-class treatment in the US for patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior lines of therapy. Immunotoxins are a class of anticancer agents that combine the selectivity of antibodies to target drug delivery and the potency of toxins to kill target cancer cells.4 Moxetumomab pasudotox is composed of a binding portion of an anti-CD22 antibody fused to a toxin. CD22 is a B-lymphocyte restricted transmembrane protein with a higher receptor density in HCL cells relative to normal B cells, making it an attractive therapeutic target for the treatment of this cancer.5 After binding to CD22, the molecule is internalized, processed and releases its modified protein toxin that inhibits protein synthesis, leading to apoptotic cell death. Moxetumomab pasudotox has been granted Orphan Drug Designation by the FDA for the treatment of HCL.

About Hairy Cell Leukemia

HCL is a rare, incurable slow-growing leukemia in which the bone marrow overproduces abnormal B cells or lymphocytes.6 HCL can result in serious and life-threatening conditions, including infections, bleeding and anemia.7 Approximately 1,000 people are diagnosed with HCL in the US each year.8,9,10 While many patients initially respond to treatment, up to 40% will relapse.11 With no established standard of care and very few treatments available, there remains significant unmet medical need for people with relapsed or refractory HCL.12,13

About the ‘1053’ Phase III Trial

The ‘1053’ trial is a single-arm, multicenter Phase III clinical trial assessing the efficacy, safety, immunogenicity and pharmacokinetics of moxetumomab pasudotox monotherapy in patients with relapsed or refractory HCL who have received at least two prior therapies. The trial is being conducted in 80 patients across 34 sites in 14 countries.14 The primary endpoint was durable complete response (CR), defined as CR with hematologic remission (blood count normalization) for >180 days. Secondary outcome measures included overall response rate, relapse free survival, progression-free survival, time to response, safety, pharmacokinetic and immunogenic potential.14

On June 1, 2018 Elios Therapeutics, a biopharmaceutical company developing innovative autologous, particle-delivered, dendritic cell cancer vaccines, reported interim data from the ongoing prospective, randomized, double-blind, placebo-controlled Phase IIb clinical trial of the TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine in patients with Stage III and IV, resected melanoma will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 4, 2018 in Chicago, Illinois (Abstract # 9525) (Press release, Orbis Health Solutions, JUN 1, 2018, View Source [SID1234529912]).

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The planned interim analysis was conducted after the first 120 patients enrolled in the trial had been randomized and treated for at least 6 months. In the per treatment population, TLPLDC showed a meaningful 32 percent reduction in the relative risk of recurrence (TLPLDC 29.4 percent vs. placebo 43.3 percent, p = 0.07) with a median follow-up of 12.6 months. There was no difference in recurrence in the intent-to-treat population (TLPLDC 56.6 percent, placebo 54.1 percent, p=0.65) with 11.9 months median follow-up. Overall, TLPLDC was safe and well-tolerated. In the study, only 33 percent of participants experienced any adverse event, and 98.6 percent of those were grade 1 and 2 events that included injection site reactions and flu-like symptoms. No serious adverse events were reported.

"The interim data evaluating the TLPLDC vaccine as an adjuvant treatment to prevent melanoma recurrences are very encouraging, suggesting clinical activity and demonstrating an attractive safety profile," said George E. Peoples, M.D., chief medical officer at Elios Therapeutics. "These data, combined with the recently reported results of our open label Phase II study demonstrating the synergistic effects of the TLPLDC vaccine in combination with checkpoint inhibitors, suggest a strong rationale for further clinical development in a Phase III program."

Detailed results from the ongoing Phase IIb study evaluating TLPLDC will be presented on Monday, June 4, 2018:

Abstract 9525 (Poster #352): Interim analysis of a prospective, randomized, double-blind, placebo-controlled, Phase IIb trial of the TLPLDC vaccine to prevent recurrence in resected Stage III or IV melanoma patients
Presenter: John W. Myers, M.D., San Antonio Military Medical Center, Houston, TX
Data/Time: Monday, June 4, 2018 from 1:15 PM – 4:45 PM CDT
Session: Melanoma/Skin Cancers Poster Session – Hall A
About the Study Design
Elios Therapeutics is conducting a prospective, randomized, double-blind, placebo-controlled Phase IIb trial to evaluate the safety and efficacy of TLPLDC in patients with resected Stage III and IV melanoma. The primary endpoint is 2 year disease-free survival (DFS).

In the study, 120 participants were randomized (2:1) to receive either TLPLDC vaccine or placebo to prevent recurrence. TLPLDC or placebo vaccines were initiated within 3 months of completion of standard of care (SoC) therapies and were given at 0, 1, 2, 6, 12, and 18 months. Study participants were followed for recurrence per SoC. The interim analysis was pre-specified at 6 months from randomization of the 120th study participant. Survival analysis was performed on the intent-to-treat and per treatment populations. The latter excludes early recurrences during the primary vaccine series (up to 6 months).

About TLPLDC
The TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine is an autologous, personalized, therapeutic cancer vaccine designed to stimulate the immune system to recognize tumor cells and fight a patient’s specific cancer. TLPLDC is made from a patient’s own tumor and dendritic cells – the most potent antigen-presenting cells in the body. Once TLPLDC is injected, the tumor lysate-loaded dendritic cells present the tumor antigens to the immune system, stimulating the induction of tumor-specific, activated T cells that are able to find and destroy tumor cells that may remain in the body. TLPLDC is currently being studied as a monotherapy and in combination with SoC checkpoint inhibitor therapy in a Phase IIb clinical trial for the treatment of late-stage melanoma at leading academic cancer centers in the United States.

On June 1, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that it will present data on its investigational BTK inhibitor zanubrutinib, and host an investor conference call and webcast at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, BeiGene, JUN 1, 2018, View Source;p=RssLanding&cat=news&id=2352714 [SID1234527021]). The EHA (Free EHA Whitepaper) meeting will take place June 14-17, 2018 in Stockholm, Sweden.

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Investor Conference Call & Webcast Information:

Date and Time: Friday, June 15, 2018, 8:00 am EDT (Friday, June 15, 2018, 8:00 pm China Standard Time)
Dial-In Numbers: 1-844-461-9930 or 1-478-219-0535 (U.S.), 400-682-8609 or 800-870-0169 (China), 852-30114522 (Hong Kong), 65-66221010 (Singapore), 61-282239773 (Australia), 0856619361 (Stockholm), or 478-219-0535 (International).
Conference ID Number: 7756029
Webcast and Replay: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source The dial-in replay will be available approximately two hours after the conference and will be available for two days following the event. It can be accessed by dialing 1-855-859-2056 (U.S.) or 1-404-537-3406 (International), or 400-683-7185 (China).

Poster Presentations:

Title: Improved Depth of Response with Increased Follow-Up for Patients (PTS) with Waldenström Macroglobulinemia (WM) Treated with Bruton’s Tyrosine Kinase (BTK) Inhibitor Zanubrutinib
Abstract: PS1186
Date: Saturday, June 16, 2018
Time: 17:30 – 19:00 (CEST)
Presenter: Dr. Judith Trotman

Title: Pooled Analysis of Safety Data from Zanubrutinib (BGB-3111) Monotherapy Studies in Hematologic Malignancies
Abstract: PF445
Date: Friday, June 15, 2018
Time: 17:30 – 19:00 (CEST)
Presenter: Dr. Constantine Tam

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated in a broad pivotal clinical program globally and in China as a monotherapy and in combination with other therapies to treat various lymphomas.

On June 1, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission (EC) has approved Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and chemotherapy (the Perjeta-based regimen) for post-surgery (adjuvant) treatment of adult patients with HER2-positive early breast cancer (eBC) at high risk of recurrence (Press release, Hoffmann-La Roche, JUN 1, 2018, View Source [SID1234527039]). High risk of recurrence is defined as lymph node-positive or hormone receptor-negative disease. The Perjeta-based regimen should be administered for a total of one year (up to 18 cycles) as part of a complete regimen for eBC and regardless of the timing of surgery.

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HER2-positive breast cancer affects almost 100,000 women in Europe each year.1,2 The majority of these cases are diagnosed at an early stage, when the aim of treatment is cure.3,4 While significant advances have been made in treating HER2-positive eBC, around one in four patients treated with Herceptin and chemotherapy will eventually see their disease return in the long-term.5 It is estimated that two out of three cases of HER2-positive advanced breast cancer (aBC) are a result of recurrence, as opposed to aBC being the initial diagnosis.6 There is no cure for breast cancer that recurs and reaches an advanced stage; in these cases, treatment is aimed at prolonging life for as long as possible.7

"Despite advances in the treatment of HER2-positive early breast cancer, many people still have a recurrence and progress to an incurable stage. In the early breast cancer setting, where the ultimate goal is cure, it is critical that we continue building on existing therapies," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Today’s approval is great news, as we believe the Perjeta-based regimen has the potential to make a significant impact on the lives of people with HER2-positive early breast cancer who are at high risk of recurrence. We are committed to working with EU member states to ensure the Perjeta-based regimen is available to eligible patients as soon as possible."

"Some patients with early HER2-positive breast cancer are more likely to relapse than others, despite available treatments. Perjeta builds on the efficacy we have already seen with Herceptin and provides a clinically meaningful reduction in the risk of the breast cancer returning or death, for patients at high risk of recurrence," explained José Baselga, MD, PhD, Physician-in-Chief, Memorial Hospital, Memorial Sloan Kettering Cancer Center. "The only setting where we can potentially cure HER2-positive breast cancer is at the early stage, so the availability of new treatment options is great news for patients."

The EC approval is based on results from a large phase III study (APHINITY), involving over 4,800 people with HER2-positive eBC8, which showed that the Perjeta-based regimen significantly reduced the risk of invasive breast cancer recurrence or death (invasive disease-free survival, iDFS) compared to Herceptin and chemotherapy alone in the overall study population.8 At the time of primary analysis, the Perjeta-based regimen showed the greatest benefit in certain patients who are at high risk of recurrence:8

For patients with lymph node-positive disease, the risk of recurrence or death was reduced by 23% with the Perjeta-based regimen (HR=0.77; 95% CI 0.62-0.96, p=0.019).*
Among patients with hormone receptor-negative disease, the Perjeta-based regimen reduced the risk of recurrence or death by 24% (HR=0.76; 95% CI 0.56-1.04, p=0.085).*
The safety profile of the Perjeta-based regimen was consistent with that seen in previous studies, with a low incidence of cardiac events and no new safety signals.8

In the eBC setting, treatment may be given before surgery (neoadjuvant treatment) to shrink tumours and after surgery (adjuvant treatment) to help prevent the cancer from returning.9 The Perjeta-based regimen is already licensed in the EU, US and many other countries as a neoadjuvant treatment.10,11 The adjuvant approval means that eligible patients with HER2-positive eBC in Europe should be treated with the Perjeta-based regimen for a total of one year as part of a complete regimen for eBC, regardless of the timing of surgery. The Perjeta-based regimen is already approved in the US and several other countries for adjuvant treatment of HER2-positive eBC at high risk of recurrence.10

The combination has also been previously approved for the treatment of people with advanced HER2-positive breast cancer, where it has been shown to significantly extend survival compared to Herceptin and chemotherapy alone.10,11

On 30 April, the EC also approved the use of Perjeta with a subcutaneous (SC) formulation of Herceptin as an alternative to the previously approved co-administration of Perjeta with Herceptin intravenous (IV) formulation.11 The Herceptin SC formulation allows Herceptin to be delivered to patients in two to five minutes via an injection under the skin, compared to 30 to 90 minutes required for the original IV formulation.12

Perjeta works in combination with Herceptin to provide a more comprehensive, dual blockade of the HER2 receptor, thus preventing tumour cell growth and survival.13

For more information about HER2-positive breast cancer and the goals of treatment, visit our Breast Cancer Hub on roche.com.

* Prespecified subgroup analyses without adjusting for multiple comparisons. Results are considered descriptive.

About APHINITY8
APHINITY (Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer, NCT01358877/ BO25126/ BIG 4-11) is an international, phase III, randomised, double-blind, placebo-controlled, two-arm study evaluating the efficacy and safety of Perjeta plus Herceptin and chemotherapy, compared to Herceptin and chemotherapy, as adjuvant therapy in 4,805 people with operable HER2-positive eBC. The primary efficacy endpoint of the APHINITY study is invasive disease-free survival (iDFS), which in this study is defined as the time a patient lives without return of invasive breast cancer at any site or death from any cause after adjuvant treatment. Secondary endpoints include cardiac and overall safety, overall survival, disease-free survival and health-related quality of life. The study will continue to follow participants for ten years.

At the time of the primary analysis, with a median follow-up of 45.4 months, the Perjeta-based regimen significantly reduced the risk of invasive breast cancer recurrence or death by 19% compared to Herceptin and chemotherapy alone in the overall study population (HR=0.81, 95% CI 0.66-1.00, p=0.045). Estimates of iDFS rates were 94.1% vs. 93.2% at three years and 92.3% vs. 90.6% at four years† in Perjeta-treated patients vs. placebo-treated patients, respectively.

The subgroup results were as follows:

Lymph node-positive subgroup (HR=0.77, 95% CI 0.62-0.96)*
Estimate of iDFS at three years 92.0% vs. 90.2%
Estimate of iDFS at four years 89.9% vs. 86.7%†
Lymph node-negative subgroup (HR=1.13, 95% CI 0.68-1.86)*
Estimate of iDFS at three years 97.5% vs. 98.4%
Estimate of iDFS at four years 96.2% vs. 96.7%†
Hormone receptor-negative subgroup (HR=0.76, 95% CI 0.56-1.04)*
Estimate of iDFS at three years 92.8% vs. 91.2%
Estimate of iDFS at four years 91.0% vs. 88.7%†
Hormone receptor-positive subgroup (HR=0.86, 95% CI 0.66-1.13)*
Estimate of iDFS at three years 94.8% vs. 94.4%
Estimate of iDFS at four years 93.0% vs. 91.6%†
The most common severe (Grade 3-4) side effects with the Perjeta-based regimen are low levels of white blood cells with or without a fever, diarrhoea, decrease in certain types of white blood cells, decrease in red blood cells, fatigue, nausea and mouth blisters or sores. The most common side effects are diarrhoea, nausea, hair loss, fatigue, nerve damage and vomiting.

* Prespecified subgroup analyses without adjusting for multiple comparisons. Results are considered descriptive.

† iDFS at four years was calculated based on data available at the time of primary analysis with median follow-up of 45.4 months.

About Perjeta
Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers.14,15 Perjeta is designed specifically to prevent the HER2 receptor from pairing (or ‘dimerising’) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumour growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of HER signalling pathways, thus preventing tumour cell growth and survival.13,16