On December 10, 2021 Caring Cross, a 501(c)(3) non-profit dedicated to accelerating the development of advanced medicines and enabling access to cures for all patients, everywhere, reported that Nature Communications has published a scientific manuscript highlighting research demonstrating the effectiveness of place-of-care manufacturing of anti-CD19 CAR T cells for treatment of B-cell malignancies (Press release, Caring Cross, DEC 10, 2021, View Source [SID1234597013]). Place-of-care manufacturing is defined as near the point of patient treatment allowing cell products to be produced and infused without need for cryopreservation.

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The manuscript, entitled, "Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients," reported that novel CD19-targeting CAR-T cells (CAR19-T cells) similarly manufactured using automation at separate sites in Cleveland, USA and Moscow, Russia achieved complete response rates of 73% in adult B-cell Lymphoma (NHL) and 89% in pediatric B-cell Acute Lymphocytic Leukemia (ALL), respectively. For NHL complete responders, the one-year survival rate was 92.9%, with a median duration of response yet to be reached. For ALL complete responders with a median follow-up of 17 months, the one-year survival rate was found to be 79.2% with a median duration of response of 10.2 months. Based on these findings, it was concluded that use of place-of-care manufactured CAR-T cell products results in clinical outcomes that are effective in the treatment of patients with B-cell malignancies.

Dr. Marcos de Lima, Director of Stem Cell Transplantation and Cellular Therapy at The Ohio State University Medical Center, and one of the lead investigators on the clinical trial, commented: "Our studies show that place-of-care manufacture of CAR-T cells results in a consistent cell product and produces effective clinical outcomes, despite being manufactured in two disparate clinical centers located in the US and Russia. We were able to make fresh CAR-T cells in as little as 8 days, which is very important for patients with rapidly progressing disease. We therefore conclude that place-of-care manufacture of CAR-T cells is a valid and valuable model for the manufacture and distribution of CAR-T cells among multiple clinical centers, and particularly important for patients with rapidly progressive, symptomatic lymphoma and ALL."

In addition to demonstrating that place-of-care manufacture of CAR-T cells results in a consistent cell product and effective clinical outcomes, the research team determined that fresh CAR19-T cells, which can only be manufactured at the place-of-care, reduce tumor burden faster in vivo in NSG mice than cryopreserved CAR19-T cells, immediately reducing the tumor burden, while frozen CAR19-T cells first permitted tumor growth before controlling growth. Moreover, the researchers found that place-of-care manufacture of CAR19-T cells resulted in a highly comparable CAR-T cell product composition between the multiple clinical centers and a low production failure rate, demonstrating the robustness of the manufacturing process.

Dr. Michael Maschan, Director of the Department of Hematopoietic Stem Cell Transplantation at the Dmitriy Rogachev National Center for Pediatric Hematology and Oncology in Moscow, Russia, commented: "Place-of-care manufacturing of CAR-T cells offers several advantages over centralized manufacturing, including reduced vein-to-vein time due to lack of transport to a centralized facility and the ability to infuse fresh and not necessarily cryopreserved products. Simplified logistics increases the flexibility to make decisions based upon patient disease status, for example split-dosing in the instance of high tumor burden. The high response rates we have seen in our clinical trials are outstanding considering that we were able to essentially treat all-comers due to the short manufacturing times of patient-derived CAR-T cell products, which are only possible when they are manufactured at the place-of-care. This has tremendous benefits for patients, particularly those with advance disease that need to be treated as soon as possible. We are delighted with the clinical results to date and look forward to future innovations to further improve patient outcomes."

Dr. Boro Dropulić, Executive Director of Caring Cross, commented: "This is the first study that definitively demonstrates the feasibility of place-of-care manufacturing of gene-modified cell products between muliple centers. We show that when the same device, materials, reagents and protocols are used to manufacture CAR-T cells, even between two disparate clinical centers, the gene-modified cell products are highly consistent with a low product failure rate. The clinical outcomes for patients were especially remarkable considering that almost all the patients enrolled were treated, even patients that otherwise would not be eligible due to their advanced disease, demonstrating the enormous value of this approach. Place-of-care manufacturing also offers the potential to dramatically reduce the cost of these transformational therapies to a fraction of their current cost due to obviating the need for transportation and the cost of multiple layers of quality and custodial assurance that are required for centralized manufactured CAR-T cell products. The next step will be to expand CAR-T cell clinical trials to include more clinical centers and support the development of regulatory pathways for the approval of CAR-T and other gene-modified cellular products that are manufactured at the place-of-care."

The full paper may be accessed via the Nature Communications website at View Source

On December 10, 2021 Exicure, Inc. (NASDAQ: XCUR) reported the results of its previously disclosed independent internal investigation and a number of strategic actions aimed to reduce cash spend and prioritize the Company’s therapeutic pipeline (Press release, Exicure, DEC 10, 2021, View Source [SID1234596793]).

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The Audit Committee of the Board of Directors of the Company (the "Audit Committee") reported the findings of the internal investigation initiated and overseen by the Audit Committee and conducted by outside counsel in connection with alleged improprieties that Grant Corbett, Ph.D., the Company’s former Group Lead of Neuroscience, claimed to have committed with respect to the Company’s XCUR-FXN preclinical program.

The results of the investigation are summarized below.

Beginning in the autumn of 2020, Dr. Corbett misreported raw data from certain research and development experiments related to XCUR-FXN;
Dr. Corbett misreported the results of at least three different experiments that were conducted through at least February 2021;
The misreported data related solely to efficacy rather than safety of XCUR-FXN;
The misreported data was included in various public presentations and SEC filings from as early as January 7, 2021 through as late as August 12, 2021;
Dr. Corbett acted alone in misreporting the data, without the assistance or knowledge of anyone else at the Company, including Company management and other research and development employees and did not inform anyone at the Company of his actions until his resignation in November 2021;
Company management reasonably relied on Dr. Corbett’s analysis when making public statements that included Dr. Corbett’s misreported data; and
No other Company program was impacted by Dr. Corbett’s misreporting of the XCUR-FXN data.
After a review of the Audit Committee’s findings from the investigation and in combination with a previously initiated strategic review of the Company’s business plans and objectives and its existing cash resources, the Company’s Board of Directors has implemented the following approved plan:

A staggered workforce reduction of approximately 50%, expected to be completed by January 2022;
Discontinuation of further enrollment and the ethical wind down of the Company’s ongoing Phase 1b/2 cavrotolimod (AST-008) clinical trial in patients with solid tumors
Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia
Restructuring and realignment of the Company’s executive team as follows, effective today:
Brian C. Bock, the Company’s former Chief Financial Officer, has been appointed as the Company’s President and Chief Executive Officer, replacing David Giljohann, and was appointed as a member of the Board.
Dr. David Giljohann, the Company’s former Chief Executive Officer, has resigned from the Board and will serve as Chief Technology Officer through January 31, 2022.
Matthias Schroff, the Company’s former Chief Operating Officer, has assumed the new role of Chief Scientific Officer;
Sarah Longoria, the Company’s former Vice President of Human Resources has been appointed as the Company’s Chief Human Resources Officer and Chief Compliance Officer; and
Douglas Feltner, M.D., the Company’s Chief Medical Officer, has agreed to assist in the wind down of the cavrotolimod and XCUR-FXN programs and will depart the Company on January 31, 2022.
Exicure expects to realize approximately $6.0 million in employee related cost savings in 2022, plus additional costs relating to the elimination of the cavrotolimod and XCUR-FXN programs. The Company estimates that it will incur total expenses relating to the restructuring of approximately $1.2 million, consisting of severance and termination-related costs and expects to record a significant portion of these charges in the fourth quarter of 2021.

The Company intends to align its research and development resources to support (i) the development of its preclinical program targeting SCN9A for neuropathic pain, (ii) the continued advancement of its partnered programs with Ipsen Biopharm Limited to develop SNA-based treatments in neuroscience targeting Huntington’s disease and Angelman syndrome, (iii) its continued advancement of its partnered program with AbbVie to develop SNA-based treatments for hair loss disorders, as well as (iv) the continued research and development of other undisclosed therapeutic product candidates.

The Company also announced a prepayment of $10.0 million of its outstanding loans under its senior secured term loan debt facility with MidCap Financial Trust, as agent, and Silicon Valley Bank (SVB), leaving a remaining outstanding balance of $7.5 million, which will remain subject to the existing terms under the loan facility.

"This has been a difficult time for all of our stakeholders and Exicure employees. I want to first thank the employees impacted by our workforce reduction for their significant contributions in pursuing treatments for patients with unmet medical needs and wish them success in their future endeavors. Although this unfortunate event will have residual effects, I strongly believe there is great value to be unlocked at Exicure with our proprietary Spherical Nucleic Acid (SNA) technology, and I look forward to advancing our promising programs in pain and other neuroscience diseases and continuing to closely work with our partners to develop innovative therapies for the treatment of genetic disorders," stated Brian Bock, President and Chief Executive Officer, Exicure.

"On behalf of the Board of Directors, I want to thank David Giljohann for his discoveries and contributions to the development of our proprietary SNA architecture, commitment in building Exicure from the ground up and leadership during his time at the Company," said Tim Walbert, Chairman of the Board, Exicure. "We look forward to working closely with Brian Bock as he assumes leadership of the Company. The Board believes Brian’s disciplined approach as well as his financial and investment banking background make him well suited to develop the new strategic path for Exicure and navigate the Company through the next phase in the Company’s evolution."

On December 10, 2021 Hologic, Inc. (Nasdaq: HOLX) and its subsidiary, Biotheranostics, Inc., reported new data demonstrating that Breast Cancer Index (BCI) not only predicts preferential recurrence-prevention benefit from extended endocrine therapy (EET), but also predicts the overall benefit/risk and likelihood of improved health outcomes from EET in certain hormone receptor positive (HR+) patients (Press release, Hologic, DEC 10, 2021, View Source [SID1234596792]). New data also confirm two biomarkers used in BCI are interconnected molecular drivers of assessing recurrences in HR+ breast cancer. These findings were presented in Spotlight Sessions at the 2021 San Antonio Breast Cancer Symposium (SABCS), which is being held from December 7-10.

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"Extended endocrine therapy often comes with tolerability challenges and even significant adverse events," said study author Marc Buyse, ScD, Associate Professor of Biostatistics at Hasselt University in Belgium. "We found the data to have considerable implications for patient compliance and joint decision-making with their healthcare providers, as patients have a more comprehensive picture of the net benefit of staying on EET so they can better assess the challenges that can come with treatment."

BCI Significantly Predicts Net Treatment Benefit (NTB) of EET in HR+ Breast Cancer

Research has shown that EET may reduce the long-term risk of recurrence in HR+ breast cancer, but treatment is often accompanied by serious adverse events (AEs), such as bone toxicity, endometrial cancer, embolisms, heart disease and more.1-3 The NTB study, which examined novel patient subset data (N=908 HR+ patients) from the Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) study, sought to determine the ability of BCI to predict the net benefit from 2.5 years vs. 5 years of EET. These data suggest patients should consider EET if they have a High HOXB13/IL17BR (H/I) result, and it confirms there is a significant NTB from EET for patients even when balanced against more serious AEs (i.e., Grade 3 or higher).

BCI Biomarkers Independently Contribute to its Ability to Predict EET Benefit

While clinical and pathologic factors are prognostic, they do not reliably predict benefit from EET like BCI [H/I] does.1-4 The Molecular Grade Index (MGI) study assessed the relationship of proliferation (MGI) and endocrine response (H/I) to further support how the BCI assay works. These data confirmed that the two biomarkers contributing to BCI’s risk assessment (H/I and MGI) drove tumor biology, thus validating BCI’s role in offering personalized extended endocrine decisions based on the individual patient’s tumor.

"These data analyzing H/I and MGI genes solidify our understanding of the relationship between these two critical components of BCI," said study author Reshma Mahtani, DO, Professor of Medicine at the University of Miami, Sylvester Comprehensive Cancer Center. "The insights confirm H/I and MGI are interdependent contributors of risk and benefit thus both necessary elements working in combination to determine risk of recurrences in HR+ breast cancer, further ensuring providers are equipped to make informed prognoses in routine care with BCI."

About Breast Cancer Index

Breast Cancer Index is a gene expression-based test uniquely positioned to provide information to help physicians individualize treatment decisions for patients with early-stage, HR+ breast cancer. This breakthrough test helps oncologists and patients navigate the difficult trade-offs between taking steps to prevent recurrence of their disease and facing significant side effects and safety challenges related to unnecessary treatment. Breast Cancer Index has guideline designation from the American Joint Committee on Cancer for cancer staging based on molecular profile. ASCO (Free ASCO Whitepaper), NCCN, the European Group on Tumor Markers (EGTM) and St. Gallen acknowledge Breast Cancer Index as a biomarker to inform the chemotherapy decision; and NCCN and EGTM acknowledge Breast Cancer Index as a biomarker to inform the extended endocrine treatment decision. It is the only validated, commercially available test that predicts benefit from extended endocrine therapy. Breast Cancer Index is intended for routine clinical use, and treatment decisions based on results are the responsibility of the physician. It is a laboratory developed test (LDT) performed in a CLIA-certified and CAP-accredited diagnostic laboratory and is not required to be cleared or approved by the US Food and Drug Administration. For more information, visit www.breastcancerindex.com.

On December 10, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported Conditional Marketing Authorisation (CMA) of RYBREVANT ▼ (amivantamab) for the treatment of adult patients with advanced NSCLC with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations, after failure of platinum-based therapy (Press release, Johnson & Johnson, DEC 10, 2021, View Source; [SID1234596782]).1 Amivantamab is the first approved treatment in the European Union specifically targeting EGFR exon 20 insertion mutations for NSCLC.1,2,4

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"Patients with NSCLC harbouring EGFR exon 20 insertion mutations represent a specific population who have been underserved by current treatment options that are limited in both number and efficacy.5 The decision made by the European Commission represents an important milestone and recognises that amivantamab offers a new treatment specifically targeted for patients with this alteration," said Antonio Passaro, M.D., Ph.D, Medical Oncologist at the Division of Thoracic Oncology of the European Institute of Oncology in Milan, Italy.†

The CMA is based on results from the Phase 1 CHRYSALIS study, a multicentre, open-label, clinical study evaluating amivantamab as a monotherapy in patients after previous treatment with platinum-based therapy, which demonstrated efficacy and a generally well-tolerated safety profile.‡4,6 The investigator-assessed overall response rate was 37 percent (95 percent CI, 28% – 46%), with a median duration of response of 12.5 months (95 percent CI, 6.5 – 16.1) and 64 percent of patients having a duration of response greater than or equal to 6 months.4 These results were consistent with those reported by blinded independent central review assessment, which showed an overall response rate of 43 percent (34% – 53%), with a median duration of response of 10.8 months (95 percent CI, 6.9 – 15.0) and 55 percent of patients having a duration of response greater than or equal to 6 months.4

Analysis showed the median progression-free survival (time experienced without progression or death) was 8.3 months (95 percent CI, 6.5 – 10.9) and the median overall survival in patients treated with amivantamab was 22.8 months (95 percent CI, 14.6 – not reached).6

The most common adverse events (AEs) at all grades included rash (76 percent), infusion-related reactions (67 percent) and nail toxicity (47 percent), and these were predominantly Grade 1-2.4 Treatment-related discontinuations due to adverse events were seen in three percent of patients.4 Ninety-nine percent of infusion-related reactions occurred with the first infusions and rarely impacted the ability to continue with subsequent treatments (1.1 percent led to treatment discontinuation).4

"This marketing authorisation addresses a high unmet need by bringing a new treatment option to this patient population and their healthcare professionals for the first time in Europe. It is an important step towards our goal to deliver innovative therapies that will transform the trajectory of lung cancer," commented Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC.

Conditional marketing authorisation is the approval of a medicine that addresses unmet medical needs of patients based on less comprehensive data than normally required, where the benefit of immediate availability of the medicine outweighs the risk, and the applicant is able to provide comprehensive clinical data in the future.7 This CMA follows other recent approvals for amivantamab, including the U.S. Food and Drug Administration (FDA), who approved the treatment in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy.8 Additional regulatory applications have been submitted and are being reviewed by other regulatory bodies worldwide.

"We are committed to changing the face of cancer care," said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, Johnson & Johnson. "At Janssen, we’re striving to transform long-term patient outcomes and improve quality of life with the right treatment, for the right patient, at the right time."

† Dr Passaro has previously provided paid consultancy services for Janssen in relation to research and advisory boards. He has not been compensated for any media work.

‡ Results reported in the SmPC are from 114 patients with a median follow up of 12.5 months.4 Results reported in Park et al are from 81 patients and a median follow up of 9.7 months.6 Not all efficacy endpoints were reported in the SmPC.4,6

About Amivantamab
Amivantamab is a fully-human EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating and resistance EGFR mutations and MET mutations and amplifications, approved for patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations after failure of platinum-based therapy.1,9,10,11,12 Amivantamab is being studied in multiple clinical trials, including:13

the Phase 1/1b, CHRYSALIS-2 (NCT04077463) study assessing the combination of amivantamab and lazertinib in patients who have progressed after treatment with osimertinib and chemotherapy, as well as lazertinib as a monotherapy14
as first-line therapy in the Phase 3 MARIPOSA (NCT04487080) study assessing amivantamab in combination with lazertinib, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), against osimertinib and against lazertinib alone in untreated advanced EGFR-mutated NSCLC15
the Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of lazertinib, amivantamab and carboplatin-pemetrexed vs. with carboplatin-pemetrexed in participants with locally advanced or metastatic EGFR Exon 19del or Exon 21 L858R substitution NSCLC after osimertinib failure16
the Phase 3 PAPILLON (NCT04538664)study assessing amivantamab in combination with carboplatin-pemetrexed vs carboplatin-pemetrexed for patients with advanced or metastatic EGFR-mutated NSCLC with exon 20 insertion mutations17
the Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery with the aim to find effective solutions that positively impact patient management.18
About the CHRYSALIS Study
CHRYSALIS (NCT02609776) is an open-label, multicentre, first-in-human Phase 1 study to evaluate the safety, pharmacokinetics and preliminary efficacy of amivantamab as a monotherapy, in combinations with lazertinib and in combination with platinum-based chemotherapy, in patients with advanced NSCLC with various EGFR mutations.3 In the study, investigators assessed efficacy using overall response rate per Response Evaluation Criteria in Solid Tumours Version 1.1* (RECIST v1.1), clinical benefit rate, median duration of response and median progression-free survival, as well as the safety profile of amivantamab.3,19

The study will enrol 780 patients with advanced NSCLC.3 The study consists of two parts: the first consists of amivantamab monotherapy and combination dose escalations, and the second consists of amivantamab monotherapy and combination dose expansions.3

The first cohort of participants received intravenous infusions of amivantamab as monotherapy.3

*RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumours, which is a standard way to measure how well solid tumours respond to treatment and is based on whether tumours shrink, stay the same or get bigger.3

About Non-Small Cell Lung Cancer (NSCLC)
In Europe, it is estimated that 477,534 patients were diagnosed with lung cancer in 2020, with around 85 percent diagnosed with NSCLC.20,21 Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined.20

The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.21 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase supporting cell growth and division.22 EGFR mutations are present in 16 to 19 percent of Caucasian patients with NSCLC and present in 37 to 41 percent of Asian patients who have NSCLC adenocarcinoma.23 The five-year survival rate for all people with metastatic NSCLC and EGFR mutations who are treated with EGFR TKIs is less than 20 percent.24 Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of 8 percent in the frontline setting, which is worse than patients with EGFR exon 19 deletions or L858R mutations, who have a real-world five-year OS of 19 percent.25

On December 10, 2021 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported an update from its Phase II SUMMIT trial at the ongoing 2021 San Antonio Breast Cancer Symposium (SABCS) Annual Meeting (Press release, Puma Biotechnology, DEC 10, 2021, View Source [SID1234596781]). The data presented was from the cohort of patients with hormone receptor-positive, HER2-mutant metastatic breast cancer, exposed to CDK4/6 inhibitors, and treated with a combination of neratinib with fulvestrant and trastuzumab and a separate cohort of patients with metastatic triple negative breast cancer with a HER2 mutation treated with the combination of neratinib plus trastuzumab. The presentation, entitled "Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial," is being presented at an oral session (GS4-10) by Komal Jhaveri, MD, FACP, Medical Oncologist at Memorial Sloan Kettering Cancer Center, on December 10 at 11:00 a.m. CST. A copy of this oral presentation is available on the Puma Biotechnology website, View Source

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The Phase II SUMMIT 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 (ERBB2) mutations or lung cancers with EGFR exon 18 mutations (NCT01953926). In the HER2-mutant, hormone receptor (HR)-positive, metastatic breast cancer cohort, patients who have previously received CDK4/6 inhibitors were previously enrolled in a non-randomized cohort and received 240 mg of neratinib per day, 500 mg fulvestrant on day 1 and 15 of Cycle 1 and then 8mg/kg trastuzumab every 4 weeks initially and then 6mg/kg trastuzumab every 3 weeks thereafter. In the HER2-mutant, triple negative metastatic breast cancer (TNBC) cohort, patients received 240 mg of neratinib per day and 8mg/kg body weight trastuzumab initially and then 6mg/kg trastuzumab every 3 weeks. All patients received anti-diarrheal prophylaxis with loperamide alone for the first two treatment cycles.

The SUMMIT trial was later amended to randomize hormone receptor-positive, HER2-mutant metastatic breast cancer patients to receive either: (i) the combination of neratinib (N), trastuzumab (T) and fulvestrant (F), (ii) the combination of fulvestrant and trastuzumab, or (iii) fulvestrant alone. Once randomized, patients received either neratinib plus fulvestrant plus trastuzumab, fulvestrant plus trastuzumab, or fulvestrant in 1:1:1 ratio. All patients received anti-diarrheal prophylaxis with loperamide alone for the first two treatment cycles.

In the non-randomized cohort, for the 26 patients with HR+, HER2-mutated MBC who had previously received CDK4/6 inhibitors, the efficacy results showed that for the patients who received neratinib plus fulvestrant plus trastuzumab, 12 patients (46.2%) experienced a confirmed objective response, all of which were partial responses, and 15 patients (57.7%) 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 14.4 months and the median progression-free survival was 8.2 months (Table 1).

For the randomized portion of the trial, for the patients with HR+, HER2-mutated MBC who had previously received CDK4/6 inhibitors, no patient in either the fulvestrant plus trastuzumab or fulvestrant alone arm experienced a confirmed objective response. In the 7 randomized patients who received the combination of neratinib, trastuzumab and fulvestrant, 2 patients (28.6%) experienced a confirmed objective response, including one complete response (14.3%) and one partial response (14.3%), and 2 patients (28.6%) 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 not reached and the median progression-free survival was 6.2 months (Table 1).

For all 33 patients with HR+, HER2-mutated MBC, who had previously received CDK4/6 inhibitors, who received the combination of neratinib plus trastuzumab plus fulvestrant, the efficacy results showed that 14 patients (42.4%) experienced a confirmed objective response, including one complete response (3.0%) and 13 partial responses (39.4%), and 17 patients (51.5%) 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 14.4 months and the median progression-free survival was 7.0 months (Table 1).

Based on the results from the randomized portion of the trial, for patients with hormone receptor-positive, HER2-mutant metastatic breast cancer, the Independent Data Monitoring Committee (IDMC) recommended closing enrollment to the fulvestrant plus trastuzumab and fulvestrant alone arms of the trial and recommended continuing enrollment in the neratinib plus trastuzumab plus fulvestrant arm of the trial. To date, the Company has enrolled 19 additional patients in this triplet arm of the trial.

For the 18 patients with HER2-mutant triple negative breast cancer (TNBC) who received fulvestrant plus trastuzumab, 6 patients (33.3%) experienced a confirmed objective response, including one complete response (5.6%) and 5 partial responses (27.8%), and 7 patients (38.9%) 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 has not been reached and the median progression-free survival was 6.2 months (Table 2).

The safety profile observed in patients treated with neratinib in the SUMMIT study was consistent with that observed previously in metastatic patients with HER2 amplified tumors. The interim safety results of the study showed that the most frequently observed adverse event was diarrhea. For the 33 safety-evaluable HR-positive breast cancer patients who received the combination of neratinib plus trastuzumab plus fulvestrant, 15 patients (45.5%) reported grade 3 diarrhea. One patient (3.0%) permanently discontinued neratinib due to diarrhea. For the 18 safety-evaluable triple negative breast cancer patients who received the combination of neratinib plus trastuzumab, 3 patients (16.7%) reported grade 3 diarrhea. No patient permanently discontinued neratinib due to diarrhea.

"For patients treated with CDK4/6 inhibitors without seeing tumor reversal, combination therapy with neratinib, fulvestrant and trastuzumab presents a promising new treatment option," said Dr. Jhaveri. "Neratinib is not only effective in treating early stage HER2-positive breast cancer but has been seen as being efficacious in helping combat secondary HER2 mutations as well."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "We are pleased to see the activity of neratinib in both the hormone receptor-positive and triple negative breast cancer cohorts of the SUMMIT trial. We look forward to obtaining data from the 19 additional patients who have been enrolled post expansion of the neratinib plus trastuzumab plus fulvestrant arm of the randomized trial, as per the IDMC, which we anticipate we will be able to present in the first half of 2022."

About HER2-Positive Breast Cancer

Up to 20% of patients with breast cancer tumors over-express the HER2 protein (HER2-positive disease) and in the ExteNET study, 57% of patients were found to have tumors that were hormone-receptor positive. 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 recurring, up to 25% of patients treated with trastuzumab experience recurrence within 10 years, the majority of which are metastatic recurrences.

About Puma Biotechnology

Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licenses the global development and commercialization rights to PB272 (neratinib, oral), PB272 (neratinib, intravenous) and PB357. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the 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 completion of prior adjuvant trastuzumab-based therapy. NERLYNX is a registered trademark of Puma Biotechnology, Inc.

Further information about Puma Biotechnology may be found at www.pumabiotechnology.com.

Important Safety Information Regarding NERLYNX (neratinib) U.S. Indication

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated:

As a single agent, for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.
In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2 based regimens in the metastatic setting.
CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Manage diarrhea through either NERLYNX dose escalation or loperamide prophylaxis. If diarrhea occurs despite dose escalation or loperamide, treat with loperamide, 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 (reported in ≥ 5% of patients) were as follows:

NERLYNX as a single agent: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection.
NERLYNX in combination with capecitabine: Diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms.
To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) 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. Separate NERLYNX by at least 3 hours with antacids. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists. Or separate NERLYNX by at least 3 hours with antacids.
Strong CYP3A4 inhibitors: Avoid concomitant use.
P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

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

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.