On December 7, 2018 Celgene Corporation (NASDAQ: CELG) reported results from the Phase 3 AUGMENT study, showing that REVLIMID (lenalidomide) in combination with rituximab (R 2 ) has resulted in a progression-free survival (PFS) higher in patients with relapsing / refractory indolent lymphoma than patients treated with rituximab plus placebo (R-placebo) (Press release, Celgene, DEC 7, 2018, View Source [SID1234531952]). The data were presented by John Leonard during an oral presentation at the 60th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), which took place in San Diego, California.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The international randomized, double-blind phase 3 clinical study evaluated the efficacy and safety of the experimental combination of R 2 compared to rituximab plus placebo in patients (n = 358) with follicular lymphoma (n = 295) and lymphoma of the area marginal (n = 63) recurrent / refractory. In the study, the R 2 arm demonstrated a statistically significant improvement in the primary progression-free survival endpoint (PFS), assessed by an independent review board, compared to the R-placebo arm. Mean PFS was 39.4 months for patients treated with R 2 versus 14.1 months for patients treated with R-placebo (P <0.0001; HR: 0.46; 95% CI, 0.34-0.62).

«Data from the AUGMENT study, with R 2 more than doubling progression-free survival compared to rituximab monotherapy, represents a possible new and important treatment option for patients with follicular lymphoma or the relapsing / refractory marginal zone» , said John Leonard , researcher responsible for the AUGMENT study, The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology and Director of the Joint Clinical Trials Office at Weill Cornell Medicine, who also served as a consultant for Celgene.

Overall survival (OS), a secondary endpoint, showed a positive trend in terms of improvement in the R 2 arm compared to the control arm (lethal events: 16 vs 26) (HR: 0.61; 95% CI, 0, 33 to 1.13). The two-year OS rate was 93% for patients treated with R 2 and 87% for patients treated with R-placebo.

The overall response rate (ORR), another secondary endpoint, was 78% (n = 138) in the R 2 arm compared to 53% (n = 96) of the R-placebo arm, according to the independent review committee. The duration of the response (DoR) was significantly increased for R 2 compared to R-placebo with medial DoR of 37 vs 22 months respectively (P = 0.0015; HR: 0.53; 95% CI, 0.36-0 , 79).

The most frequent adverse event (AE) in the R 2 arm was neutropenia (58%), vs. 22% in the R-placebo arm. Other AEs commonly seen in more than 20% of patients included diarrhea (31% in the R 2 arm vs. 23% in the R-placebo arm), constipation (26% vs. 14%, respectively), cough (23% vs. 17% ) and fatigue (22% vs. 18%). Adverse events most commonly reported (> 10%) in the R arm 2 were neutropenia, constipation, leukopenia, anemia, thrombocytopenia and acute exacerbation of symptoms tumor ( tumor flare reaction) . During the AUGMENT study no unexpected results were observed in terms of safety.

"These data represent a new, potential treatment strategy for patients with relapsing / relapsing indolent non-Hodgkin’s lymphomas , " said Celgene’s president of Global Clinical Development, Alise Reicin . "We are anticipating the submission of authorization applications for the first quarter of 2019. to allow patients to access this important combination as soon as possible . "

The use of REVLIMID , alone or in combination with other agents, is currently not approved in any country in the treatment of follicular lymphoma or in that of marginal zone lymphoma.

Information on REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (des) is indicated for the treatment of patients with multiple myeloma (MM).

REVLIMID is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT).

REVLIMID is indicated in the treatment of patients with transfusion-dependent anemia due to myelodysplastic syndromes (MDS) at low or intermediate risk 1, associated with a cytogenetic abnormality with 5q deletion, with or without further cytogenetic abnormalities.

REVLIMID is indicated for the treatment of patients with recurrent mantle cell lymphoma (MCL) or with progression of the disease after 2 previous therapies, one of which includes bortezomib.

REVLIMID is not recommended or recommended for the treatment of patients with chronic lymphatic leukemia (LLC) outside of controlled clinical trials.

On December 7, 2018 Arvinas Inc. (Nasdaq: ARVN), a biotechnology company creating a new class of drugs based on targeted protein degradation, reported its positive preclinical data on the company’s lead clinical candidate, ARV-471, for advanced or metastatic ER-positive/HER2-negative breast cancer at the 2018 San Antonio Breast Cancer Symposium (SABCS), taking place December 4-8 in San Antonio, Texas (Poster P5-04-18; Session 5: Tumor Cell and Molecular Biology: Endocrine Therapy and Resistance) (Press release, Arvinas, DEC 7, 2018, View Source [SID1234531969]). In this study, orally administered ARV-471 demonstrated improved potency and anti-tumor activity both as a monotherapy and in combination with a CDK4/6 inhibitor, compared to current standard of care treatment regimens.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We believe that ARV-471 has the potential to be the first oral protein degrader for the treatment of patients with metastatic ER-positive/HER2-negative breast cancer, when used either as a single-agent or in combination with other routinely used anti-cancer agents," said John Houston, Ph.D., President and CEO of Arvinas. "This data reinforces our growing confidence that our PROTAC protein degraders have the potential to provide distinct advantages over existing approaches across a broad range of disease targets and to improve clinical outcomes over current standard of care. We continue to expect to initiate our Phase 1 clinical trial of ARV-471 in mid-2019."

Key highlights from the poster "ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer":

Orally bioavailable ARV-471 demonstrated potent ERa degradation in wild-type and mutant ERa-expressing cell lines.
Oral administration of ARV-471 caused near-complete ERa degradation and resulted in tumor shrinkage in an orthotopic MCF7/estradiol breast cancer preclinical model; ARV-471 demonstrated superior tumor growth inhibition and ERa degradation compared to standard-of-care agent, fulvestrant.
Combination of ARV-471 and a CDK4/6 inhibitor demonstrated superior tumor growth inhibition when compared to the combination of fulvestrant and a CDK4/6 inhibitor.
ARV-471 inhibited growth of tamoxifen-resistant and ERa gene (ESR1) mutant tumors while also reducing tumor ERa levels.
ARV-471 displayed no ER agonist activity.

On December 6, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, is reported that updated results from a Phase II clinical trial of Puma’s drug neratinib at the 2018 San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 6, 2018, View Source [SID1234531920]). The presentation entitled, "The impact of neratinib with or without anti-diarrheal prophylaxis on health-related quality of life in HER2-positive early stage breast cancer: Analyses from the ExteNET and CONTROL trials." is being presented by Dr. Suzette Delaloge, Institut Gustave Roussy, Paris, France, at a poster session on December 6 from 7:00 – 9:00 a.m. CST. A full copy of the poster is available on the Puma Biotechnology website at www.pumabiotechnology.com.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. NERLYNX was granted marketing authorization in September 2018 by the European Commission for extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy

Diarrhea is the main side effect of neratinib. In ExteNET, where antidiarrheal prophylaxis was not mandated by the study protocol, grade 1/2 diarrhea was reported in 55% and 34% of patients in the neratinib and placebo groups, respectively, and grade 3 diarrhea occurred in 40% and 2%, respectively. Because neratinib-induced diarrhea occurs early in the course of treatment, a structured high dose regimen of loperamide prophylaxis given for one or two cycles has been introduced to better manage this side effect. The Phase II CONTROL study, conducted in the exact same setting as ExteNET, investigated the effectiveness of anti-diarrheal prophylaxis with loperamide alone or in combination with budesonide or colestipol in the prevention of neratinib-associated diarrhea.

Both ExteNET and CONTROL assessed patient-reported outcomes using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B), a validated instrument for the assessment of health-related quality of life (HRQoL) in breast cancer. Total scores of FACT-B range from 0-144, with higher scores indicating better HRQoL. A change of 7-8 points in the FACT-B total score is considered clinically meaningful. Preliminary HRQoL findings from the CONTROL study were presented in 2017 and are posted on Puma’s website at www.pumabiotechnology.com/pr20171206.html. The poster presented at SABCS reports more detailed and mature HRQoL data from CONTROL, and compares it to the HRQoL findings from the ExteNET study.

In ExteNET, 17% of patients in the neratinib group and less than 1% of patients in the placebo group discontinued treatment because of diarrhea. In CONTROL, 20% of patients in the loperamide cohort, 11% in the budesonide plus loperamide cohort, and 4% in the colestipol plus loperamide cohort discontinued treatment due to diarrhea.

The poster presentation demonstrates that in both studies decreases in FACT-B total scores seen in early months were followed by recovery towards baseline levels. Decreases in FACT-B total scores observed did not cross a clinically meaningful threshold at any time point.

In the ExteNET study, a transient decrease in FACT-B total score was observed with neratinib at month 1 (mean change from baseline, –4.6 points) followed by recovery towards baseline. Decreases were also evident in the placebo group, with mean changes from baseline ranging from –3.5 to –1.7 points during study treatment. After month 3, mean changes from baseline were similar in neratinib and placebo arms. None of these changes reached clinically meaningful thresholds (7–8 points) at any time point.

The presentation also shows that in the CONTROL study, FACT-B total scores decreased from baseline in all cohorts; mean changes from baseline ranged from –6.0 to –1.5 points over the course of study treatment. In the cohorts that had completed follow-up (loperamide, budesonide plus loperamide), the largest decreases in FACT-B total scores were evident during months 1 and 3 followed by recovery towards baseline levels. None of these changes reached clinically meaningful thresholds (7–8 points) at any time point.

An evaluation of each of the FACT-B subscales (n=5) were evaluated and this analysis suggested that physical well-being (PWB) was the only subscale where the clinically important difference (CID) threshold was crossed in both trials. In the ExteNET study, in the neratinib arm, FACT-B PWB decreased at month 1 before improving at later visits. The mean change from baseline at month 1 with neratinib was –2.9 points and was greater than clinically meaningful thresholds (2‒3 points); changes at later time-points were all less than the clinically meaningful threshold.

In the CONTROL study, decreases in FACT-B PWB were observed in all CONTROL cohorts throughout study treatment, with largest changes from baseline observed at month 1. In the loperamide alone and colestipol plus loperamide cohorts, changes reached clinically meaningful thresholds (2‒3 points) at 4 out of 5 study visits, whereas in the budesonide plus loperamide cohort, changes crossed the CID threshold during months 1 and 3 only.

Suzette Delaloge, MD, Institut Gustave Roussy, Paris, France, said, "Diarrhea is the main side effect of neratinib and can be bothersome in some patients. Although this is not a direct comparison, the confrontation of Extenet and Control data teach us how to prevent grade 3 diarrhea and how to allow better quality of life, together with better adherence of patients to this therapy."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased with the HRQoL data from ExteNET and CONTROL. We look forward to additional data from the CONTROL trial, which may continue to improve HRQoL and adherence to treatment."

About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

IMPORTANT SAFETY INFORMATION

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

On December 6, 2018 MorphoSys AG (FSE: MOR; Prime Standard Segment; MDAX & TecDAX; Nasdaq: MOR) reported its data from the ongoing single-arm phase 2 clinical trial known as L-MIND in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 in San Diego, USA (Press release, MorphoSys, DEC 6, 2018, View Source [SID1234531937]). L-MIND is designed to investigate the antibody MOR208 in combination with lenalidomide in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). MOR208 is an investigational humanized Fc-enhanced monoclonal antibody directed against CD19 and is currently in clinical development in blood cancer indications.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The L-MIND study enrolled patients with r/r DLBCL, who are ineligible for HDC and ASCT, after up to three prior lines of therapy, with at least one prior therapy including an anti-CD20 targeting therapy, such as rituximab. The updated interim data reported today (cut-off date June 5, 2018) included all 81 patients enrolled in the L-MIND trial, with a median observation time of 12 months. Efficacy results in this update are based on assessment by the investigators for all 81 patients. Patients enrolled had a median age of 72 years and had received a median of two prior treatment lines.

The data showed a response in 47 out of 81 patients (overall response rate, or ORR, 58%), with complete responses (CR) in 27 (33%) and partial responses (PR) in 20 (25%) patients. The median progression-free survival (mPFS) was 16.2 months (95% confidence interval (CI) 6.3 months – not reached). Responses were durable with the median duration of response (DoR) not reached (95% CI: NR – NR) and 70% of responding patients were without progression at 12 months (12-month DoR rate: 70%, Kaplan-Meier estimate). A significant proportion of patients (37/81; 46%) were still on study treatment, with 19 having been treated for over 12 months. Median overall survival (OS) was not reached (95% CI: 18.6 months – NR); the 12-month OS rate was 73% (95% CI: 63% – 85%).

Efficacy parameters, such as response rates and median PFS showed comparable results in most patient subgroups of interest, including low/low-intermediate versus intermediate-high/high IPI score, rituximab refractory versus not refractory and primary refractory versus not refractory, amongst others.

No unexpected toxicities were observed for the treatment combination and no infusion-related reactions (IRRs) were reported for MOR208. The most frequent treatment-emergent adverse events (TEAEs) with a toxicity grading of 3 or higher were neutropenia in 35 (43%), thrombocytopenia in 14 (17%), and anemia in 7 (9%) patients each. Treatment-related serious adverse events (SAEs) occurred in 16 (19.8%) patients, the majority of which were infections or neutropenic fever. 41 (50.6%) patients required dose reduction with lenalidomide, 58 patients (72%) could stay on a daily lenalidomide dose of 20 mg or higher.

The results reported today confirm data from earlier interim analyses reported from this trial in March 2018, when 68 patients had been eligible for investigators’ efficacy assessment at the Dec 12, 2017 cut-off date.

"Patients with relapsed or refractory DLBCL who, after having failed initial therapies, are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), need more treatment options," commented Dr. Malte Peters, Chief Development Officer of MorphoSys AG. "We are encouraged by our most recent clinical data from the ongoing L-MIND trial. These support our plan to develop MOR208 in combination with lenalidomide, based on our current FDA breakthrough therapy designation, as a potential chemo-free treatment option for this patient population."

Details about the presentation on L-MIND data at ASH (Free ASH Whitepaper) 2018:

Abstract publication number: 227

Session name: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials"

Session date and time: Saturday, December 1, 2018, 4:00pm-5:30pm PST

Presentation time: 5:00pm PST

Room: Marriot Marquis San Diego Marina, Pacific Ballroom 20, San Diego, California.

MorphoSys will hold an investor & analyst event after the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 on December 5, 2018, 10:00am EST (3:00pm GMT, 4:00pm CET) in New York. The presentation, a live webcast and a replay of the webcast will be made available at View Source

About DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of malignant lymphoma worldwide and accounts for approximately 30% of all non-Hodgkin lymphomas. Between 30% and 40% of all patients with DLBCL either fail to respond to or show a relapse to initial therapy. Patients who failed frontline therapy and are not eligible to high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are reported to have a poor outcome and require more therapeutic options.

About CD19 and MOR208

CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 has been reported to enhance B cell receptor (BCR) signaling, which is assumed important for B cell survival, making CD19 a potential target in B cell malignancies.

MOR208 is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus aiming to improve a key mechanism of tumor cell killing. MOR208 has been observed in preclinical models to induce direct apoptosis by binding to CD19, which is assumed to be involved in B cell receptor (BCR) signaling.

MorphoSys is clinically investigating MOR208 as a therapeutic option in B cell malignancies in a number of ongoing combination trials. An open-label phase 2 combination trial (L-MIND study) is investigating the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Based on interim data from L-MIND, in October 2017 the U.S. FDA granted Breakthrough Therapy Designation for MOR208 plus lenalidomide in this patient population. The pivotal phase 2/3 B-MIND study is designed to investigate MOR208 in combination with the chemotherapeutic agent bendamustine in patients with relapsed/refractory DLBCL who are not eligible for high-

dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in comparison to the combination of the anti-CD20 antibody rituximab plus bendamustine. In addition, MOR208 is currently being investigated in patients with relapsed/refractory CLL/SLL after discontinuation of a prior Bruton tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib) in combination with idelalisib or venetoclax.

On December 6, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that results from an ongoing Phase II clinical trial of Puma’s drug neratinib are being presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 6, 2018, View Source [SID1234531921]). The presentation entitled, "Neratinib + fulvestrant for HER2-mutant, HR-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT trial," are being presented at a Spotlight Session by Lillian M. Smyth, M.D., Breast Medicine Service and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, an investigator of the trial.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. NERLYNX was granted marketing authorization by the European Commission for the extended adjuvant treatment of hormone receptor-positive HER2-positive early stage breast cancer in September 2018.

The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study to evaluate the safety and efficacy of neratinib administered daily to patients who have solid tumors with activating HER2 or HER3 mutations. In the HER2-mutant, HR-positive breast cancer cohort, 47 patients received 240 mg of neratinib daily in combination with fulvestrant at the labeled dose. In this cohort, 43 patients (92%) had HER2-non-amplified disease, and patients had received a median of 3 prior lines of therapy in the metastatic setting (range 0-11 prior regimens) before entering the trial. All patients had been previously treated with an endocrine agent prior to entering the study, including 25 patients (53%) who had received prior fulvestrant. Further, 20 patients (43%) received prior cyclin-dependent kinase 4/6 (CDK4/6)-inhibitor therapy.

The efficacy summary of the breast cohort that received neratinib + fulvestrant is shown in Table 1 below. The interim efficacy results from the trial showed that for the 47 efficacy evaluable patients, 14 patients (30%) experienced an objective response, which included 4 patients with a complete response and 10 patients with partial responses, and 22 patients (47%) experienced clinical benefit (clinical benefit is defined as confirmed complete response or partial response or stable disease for at least 24 weeks). The median duration of response was 9.2 months and the median progression free survival was 5.4 months. Subgroup analysis demonstrated that patients who had received prior fulvestrant or CDK4/6 inhibitor targeted therapy prior to entering the trial also benefited from treatment of neratinib + fulvestrant. Of note, 6 patients (30%) with prior CDK4/6-inhibitor exposure demonstrated confirmed responses, with the duration of responses ranging from 4.5–14.8 months. Four patients were still on treatment at the time of data reporting.

Table 1: HER2-Mutant, HR-Positive Metastatic Breast Cancer
Phase II SUMMIT Trial Efficacy Summary

Neratinib + Fulvestrant
Subgroups
All Patients
(n=47)

Prior Fulvestrant
(n=25)

Prior CDK4/6 Inhibitor-Based
Therapy (n=20)

Efficacy Endpoint a :
Objective response (confirmed)b – n 14 4 6
CR 4 0 1
PR 10 4 5
Objective response rate (95% CI) 30 (17–45) 16 (5–36) 30 (12–54)
Medianc DOR, months (95% CI) 9.2 (5.5–16.6)
DOR for each responder 9.2; 9.3*; 14.8*; 16.6 4.5; 7.3; 9.2*; 9.3*; 11.2*; 14.8*

Clinical benefitd – n 22 9 8
CR or PR 14 4 6
SD 8 5 2
Clinical benefit rate (95% CI) 47 (32–62) 36 (18–58) 40 (19–64)

Medianc PFS (95% CI) time to event, months 5.4 (3.7–9.2) 3.7 (3.5–6.9) 4.1 (1.9–10.9)

Patients with RECIST v1.1 Measurable Disease
Subgroups
Efficacy Endpoint a : All Patients
(n = 39)

Prior Fulvestrant
(n = 21)

Prior CDK4/6 Inhibitor-Based
Therapy (n=15)

Objective response (confirmed)b – n 12 4 5
CR 2 0 0
PR 10 4 5
Objective response rate (95% CI) 31 (17–48) 19 (5–42) 33 (12–62)

Medianc DOR, months (95% CI) 9.0 (4.5–16.6)
DOR for each responder 9.2; 9.3*; 14.8*; 16.6 4.5; 7.3; 9.2*; 9.3*; 14.8*

Clinical benefitd – n 18 8 6
CR or PR 12 4 5
SD 6 4 1
Clinical benefit rate (95% CI) 46 (30–63) 38 (18–62) 40 (16–68)
Medianc PFS (95% CI) time to event, months 5.4 (3.5–10.3) NA NA
a

Response is based on investigator tumor assessments per RECIST v1.1 or modified PERCIST for patients with only PET-evaluable lesions.

Overall objective response (ORR) is defined as either a complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met.

Kaplan-Meier analysis

Clinical benefit rate (CBR) is defined as confirmed CR or PR or stable disease (SD) for at least 24 weeks (within +/- 7 day visit window).

Patient still on treatment at time of data cut; DOR, duration of response; PFS, progression free survival; NA, not available

The safety profile observed in neratinib + fulvestrant-treated breast cancer patients in the SUMMIT study was consistent with that observed previously in metastatic patients with HER2 amplified tumors. With anti-diarrheal prophylaxis and management, diarrhea was not a treatment-limiting side effect in SUMMIT. The interim safety results of the study showed that the most frequently observed adverse event was diarrhea. For the 47 patients enrolled in the trial, 11 patients (23%) reported grade 3 diarrhea. The median duration of grade 3 diarrhea for those patients was 1.5 days. No patients permanently discontinued neratinib due to diarrhea.

Dr. Lillian Smyth said, "Somatic HER2 mutations represent a distinct class of oncogenic driver mutations that appear to be clinically actionable for metastatic breast cancers. The combination of neratinib plus fulvestrant therapy demonstrates encouraging clinical activity with durable responses in this heavily pretreated metastatic breast cancer patient population with HER2-mutated and hormone receptor-positive disease."

Alan H. Auerbach, CEO and President of Puma Biotechnology, added, "We are very pleased with the updated activity seen with neratinib in combination with fulvestrant in this cohort of patients with HER2-mutated breast cancer. We look forward to the further development of the combination of neratinib and fulvestrant in this patient population."