On June 4, 2021 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that results at the virtual 2021 ASCO (Free ASCO Whitepaper) Annual Meeting comparing the diarrhea mitigation strategies investigated in the Phase II CONTROL trial with the neratinib treatment arm of the ExteNET trial where diarrhea prophylaxis was not required (Press release, Puma Biotechnology, JUN 4, 2021, View Source [SID1234583592]). The presentation, entitled "Dose escalation for mitigating diarrhea: Ranked tolerability assessment of antidiarrheal regimens in patients receiving neratinib for early-stage breast cancer," is included in the Breast Cancer—Local/Regional/Adjuvant Poster Session (#536).

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The CONTROL trial is an international, open-label, Phase II study investigating the use of antidiarrheal prophylaxis or dose escalation to improve the tolerability of neratinib-associated diarrhea. The primary endpoint of the trial is the incidence of grade 3 diarrhea. Patients ≥18 years of age with stage I–IIIc HER2-positive breast cancer received neratinib (240 mg/day orally for 1 year) together with one of the regimens investigated: loperamide alone, in combination with budesonide or colestipol, or neratinib dose escalation (DE): 120 mg/day on days 1–7, 160 mg/day on days 8–14, then 240 mg/day thereafter + loperamide PRN.

In the analysis presented at ASCO (Free ASCO Whitepaper) 2021, five CONTROL cohorts that had completed follow up were evaluated for 13 endpoints related to tolerability. The DE cohort ranked the best among the CONTROL cohorts and was then compared with the neratinib arm of the ExteNET trial, which included patients ≥18 years of age with stage I–III HER2-positive breast cancer receiving neratinib 240 mg/day or matching placebo for one year, without mandated anti-diarrheal treatment. ExteNET was a multicenter, randomized, double-blind, Phase III trial (NCT00878709) of 2,840 HER2-positive early stage breast cancer patients who received neratinib after neoadjuvant and/or adjuvant therapy with chemotherapy and a trastuzumab-based regimen.

Comparison of the CONTROL DE cohort with the ExteNET neratinib arm demonstrated that grade 3 diarrhea was substantially lower in CONTROL DE compared to ExteNET (13.3% vs. 39.9%). Neratinib DE also resulted in fewer total days of grade 3 diarrhea compared to ExteNET (2.5 days vs 5 days). Dose escalation also led to fewer discontinuations due to diarrhea in the first three months of treatment compared to ExteNET (3.3% vs 14.5%). Additionally, the average duration of treatment with neratinib was much longer in the DE cohort versus ExteNET. Overall, the findings of this analysis suggest that escalating the dose of neratinib in the first 2 weeks of treatment may help patients stay on neratinib longer, allowing them the opportunity to complete the recommended 1-year of treatment.

"Dose escalation of neratinib with loperamide PRN is an effective way of minimizing the extent of grade 3 diarrhea. This strategy showed improvements in overall tolerability as compared to ExteNET and resulted in more patients being able to remain on therapy," said Gavin M. Marx, MBBS, Sydney Adventist Hospital.

"These results confirm that dose escalation of neratinib lowered the incidence and duration of grade 3 diarrhea as well as discontinuations due to diarrhea, said Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine. "Using dose escalation, the average duration of neratinib was longer (compared to ExteNET)."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "We are committed to research that seeks to understand how to improve the tolerability of neratinib. The CONTROL trial evaluated multiple diarrhea mitigation strategies and dose escalation of neratinib resulted in the best tolerability, allowing more patients to stay on treatment for the recommended duration."

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.

On June 4, 2021 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, presented results from the Phase III ExteNET trial assessing the impact of neratinib treatment duration on overall survival (OS) in patients with early stage HER2-positive breast cancer at the virtual 2021 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Puma Biotechnology, JUN 4, 2021, View Source [SID1234583591]). The presentation, entitled "Association between treatment duration and overall survival in early-stage HER2+ breast cancer patients receiving extended adjuvant therapy with neratinib in the ExteNET trial," is included in the Breast Cancer—Local/Regional/Adjuvant Poster Session (#540).

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ExteNET was a multicenter, randomized, double-blind, Phase III trial of 2,840 HER2-positive early stage breast cancer patients who received neratinib after neoadjuvant and/or adjuvant therapy with chemotherapy and trastuzumab-based treatment. Patients were randomly assigned to one year of treatment with either oral neratinib 240 mg/day or placebo.

The poster presented by Professor Beverly Moy summarizes descriptive analyses evaluating the impact of duration of neratinib on clinical outcomes including invasive disease-free survival (iDFS) and distant disease-free survival (DDFS) at 5 years, and overall survival (OS). The analyses were performed in the intention-to-treat (ITT) population and subgroups of clinical interest including the HR+/≤1 year population (patients with hormone receptor-positive (HR+) disease who initiated neratinib within 1 year after prior trastuzumab) and within that subgroup, in the no pathologic complete response (pCR) group (patients from the HR+/≤1-year population with residual disease post-neoadjuvant therapy). Efficacy outcomes in patients who completed neratinib therapy were compared with placebo (all randomized patients). Completion of therapy was defined as patients who were on treatment for ≥ 11 months. Patients who ended neratinib therapy because of disease recurrence before 11 months were also considered with those who ‘completed therapy’ to reduce guarantee-time bias.

Among patients who completed ≥ 11 months of neratinib therapy, OS (median follow-up of 8.0 years) was improved versus placebo in each of the 3 groups. In the intention-to-treat (ITT) population, 872 of 1420 patients (61.4%) in the neratinib arm completed ≥ 11 months of treatment; OS rates were 92.2% vs 90.2% in the neratinib vs placebo arms, respectively, corresponding to a 2.0% improvement (HR 0.78; 95% confidence interval (CI) 0.58-1.04). In the HR+/≤1 year patient population, 402 of 670 patients (60%) in the neratinib arm completed ≥ 11 months of treatment; OS rates were 95.2% vs 89.4% in the neratinib vs placebo arms, respectively, corresponding to a 5.8% improvement (HR 0.49; 95% CI 0.29‒0.78). In the HR+/ <1 year, no pCR group, 92 of 131 patients (70.2%) in the neratinib group completed ≥ 11 months of treatment; OS rates were 95.4% vs 82.2% in the neratinib vs placebo arm, respectively, corresponding to a 13.2% improvement (HR 0.29; 95% CI 0.10–0.68).

Neratinib also numerically improved 5-year iDFS and DDFS outcomes versus placebo in all groups: 3.3% and 2.0%, respectively, in the ITT group of patients who completed therapy; 7.4% and 5.9%, respectively, in the HR+/≤1 year subgroup who completed therapy; and 11.9% and 10.9%, respectively, in the HR+/≤1 year no pCR subgroup who completed therapy.

Importantly, completion ≥ 11 months of therapy was associated with more pronounced improvements in all endpoints evaluated. In the ITT population, the HR for OS was reduced from 0.95 to 0.78 upon completion of therapy. In the HR+/≤1-year population, the HR for OS was reduced from 0.79 to 0.49 upon completion of therapy. In the HR+/≤1-year no pCR group, the HR for OS was reduced from 0.47 to 0.29 upon completion of therapy. Consistent improvements upon completion of therapy were also seen for iDFS and DDFS.

"These descriptive findings suggest that overall survival in patients with early stage HER2-positive breast cancer patients is improved upon completion of neratinib extended adjuvant therapy. This improvement trend was observed across all groups and reflected in the iDFS measurements as well, thereby showing that a complete course of neratinib in patients with early stage HER2-positive breast cancer who are at a high risk of relapse can be beneficial," said Beverly Moy, MD, MPH, Clinical Director of the Breast Oncology Program at Massachusetts General Hospital.

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "These data show that adherence to neratinib in the extended adjuvant setting lowers the risk of recurrence and improves overall survival. These findings are consistent with previously presented data and add to the growing body of evidence supporting the use of neratinib in HER2-positive early stage breast cancer."

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.

On June 4, 2021 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company developing a new class of potent and selective precision oncology medicines, which it refers to as Pentarin miniature drug conjugates, reported data from the gastrointestinal (GI) mid-gut neuroendocrine tumors (NETs) cohort of its Phase 2 clinical trial of PEN-221, presented at the 2021 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Tarveda Therapeutics, JUN 4, 2021, businesswire.com/news/home/20210604005111/en/Tarveda-Therapeutics-Presents-Promising-Phase-2-Data-of-PEN-221-in-Gastrointestinal-Mid-gut-Neuroendocrine-Tumors [SID1234583590]).

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"The results presented at ASCO (Free ASCO Whitepaper) from the gastrointestinal mid-gut neuroendocrine cohort of the PEN-221 trial show that PEN-221 was well tolerated and demonstrated efficacy exceeding its clinical efficacy goals with a clinical benefit rate of 88.5% and median progression-free survival of 9 months," said Jeffrey Bloss, M.D., Chief Medical Officer of Tarveda. "We are encouraged by the safety and efficacy shown by PEN-221 in GI mid-gut NETs and are developing a randomized trial to further evaluate PEN-221 in this patient population."

"Gastrointestinal neuroendocrine tumors are a disease with a significant unmet need. While targeting SSTR2 receptors has been an effective strategy in treating GI NETs, there remains a need for additional therapies which delay disease progression and prolong patients’ lives," said Daniel M Halperin, M.D., Assistant Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "PEN-221 selectively binds with high affinity to SSTR2 expressed on neuroendocrine tumors, where it releases its DM1 payload directly into the tumor cells, causing cell cycle arrest and apoptosis. This approach demonstrated encouraging efficacy results in the GI mid-gut NET cohort of the Phase 2 trial and was well tolerated by patients."

The results presented had a data cutoff of July 31, 2020 and five patients remained on study at the time of the cutoff. Of the 32 patients included in these results, the first nine were treated at the Phase 1 determined maximum tolerated dose of 18 mg. After review of the safety, tolerability, and pharmacokinetic data, the regimen was amended to 8.8 mg/m2 for all subsequent patients to achieve more uniform exposures across all patients and reduce toxicity in patients with lower body-surface-area (BSA).

Trial Design

PEN-221 was administered as a one-hour intravenous infusion once every three weeks to patients with advanced SSTR2+ GI mid-gut NETs with documented radiographic progression within the six months prior to enrollment. Preliminary efficacy was assessed using RECIST 1.1. A clinically meaningful efficacy result was defined as a clinical benefit rate (CBR) > 75% and a median progression-free survival (mPFS) > 8 months.

Safety Data

A safety analysis of 32 patients demonstrated that PEN-221 was well tolerated when dosed at 8.8 mg/m2. The most frequent treatment related adverse events of any Grade were fatigue (39%), nausea (38%), diarrhea (35%), decreased appetite (30%), infusion reaction (24%), aspartate transaminase (AST)/alanine transaminase (ALT)/alkaline phosphatase (Alk Phos) increase (24%), and peripheral neuropathy (21%). Only 14 (10%) of these events were Grade 3 or greater. Grade 3 treatment related adverse events, which were reported in two or more patients, included fatigue (7.6%), ALT/AST/Alk Phos increase (7.6%), and peripheral neuropathy (3%).

Efficacy Data

PEN-221 demonstrated efficacy at 8.8 mg/m2 with a CBR of 88.5% and mPFS of 9 months. Of the 26 patients who were evaluable for response, 23 (88.5%) had stable disease (SD) reported as their best response and target lesion shrinkage was observed in 10 (38%) patients.

A randomized trial of PEN-221 in GI mid-gut NET patients is now in development.

The poster presentation is available on demand on the ASCO (Free ASCO Whitepaper) website beginning on June 4, 2021 at 9:00 AM ET. Details of the poster presentation are as follows:

Title: The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results.
Abstract Number: 4110

About PEN-221

PEN-221 is a miniature drug conjugate consisting of a peptide ligand, that is highly selective in targeting SSTR2, joined through a cleavable linker to the potent cytotoxic payload DM1. SSTR2 is overexpressed on the cell surface of a range of solid tumors including neuroendocrine tumors and small cell lung cancers. In non-clinical experiments, PEN-221 binds with high affinity and selectivity to SSTR2. On binding, PEN-221 triggers SSTR2 internalization resulting in the accumulation of the DM1 payload in tumor cells followed by cell cycle arrest and apoptosis.

PEN-221 is being evaluated in Phase 2a expansion cohorts enrolling patients with mid-gut neuroendocrine tumors, pancreatic neuroendocrine tumors, and small cell lung cancer (ClinicalTrials.gov Identifier: NCT02936323).

On June 4, 2021 Onco360, the nation’s largest independent Oncology Pharmacy, reported that it has been selected by Amgen to be a specialty pharmacy partner for LUMAKRAS (sotorasib), a new oral treatment for adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy (Press release, Onco360, JUN 4, 2021, View Source [SID1234583589]).

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"Onco360 is honored to be selected as a specialty pharmacy provider for LUMAKRAS in partnership with Amgen," said Benito Fernandez, Chief Commercial Officer, Onco360. "The recent approval of LUMAKRAS unlocks the first FDA-approved treatment option for patients with previously treated advanced or metastatic KRAS G12C-mutant NSCLC. As a provider of this key treatment, Onco360 is committed to supporting the highly specialized needs of NSCLC patients."

ABOUT METASTATIC NON-SMALL CELL LUNG CANCER

According to the National Cancer Institute’s (NCI’s) Surveillance, Epidemiology, and End Results (SEER) program, 235,760 patients will be diagnosed with lung cancer in 2021, with a corresponding 131,880 deaths. When considering all stages and histologic subtypes of the disease, the five-year overall survival (OS) of lung cancer is 21.7%. Patients with Stage IV metastatic disease have a five-year OS of only 6.3%. Unfortunately, 56% of lung cancer patients have metastatic disease upon initial diagnosis. Up to 85% of lung cancer cases are classified as NSCLC.1 Approximately 13% of NSCLC patients have KRAS G12C mutations.2

LUMAKRAS is manufactured by Amgen, a global biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies for the treatment of cancer. The FDA’s approval of LUMAKRAS comes as a result of a 124 patient subset of the Phase I/II CodeBreak 100 clinical trial (NCT03600883) which demonstrated that previously treated patients with metastatic KRAS G12C-mutant NSCLC experienced a 36% objective response rate (ORR) after LUMAKRAS ad

On June 4, 2021 Lvgen Biopharma, a biotech company focused on developing innovative immuno-oncology therapeutics, reported that it will present a Trials in Progress poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper), to be held in a virtual format from June 4 to 8, 2021 (Press release, Lyvgen Biopharma, JUN 4, 2021, View Source [SID1234583587]).

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The Trials in Progress poster presentation summarizes the safety profile, antitumor activity observed in a phase I clinical trial (NCT04130542) in collaboration with Merck & Co., Inc., Kenilworth, New Jersey, U.S.A., known as MSD outside of the U.S. and Canada. The trial is evaluating LVGN6051, a second generation 4-1BB (CD137) agonist antibody based on Lyvgen proprietary xLinkAb platform, as monotherapy or in combination with KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 therapy, in adult patients with advanced malignancies. No MTD was reached at 7 mg/kg monotherapy and 4 mg/kg q3w monotherapy was determined as RP2D. Preliminary antitumor activity in late stage cancer patients was observed. Combination with pembrolizumab induced rapid antitumor responses in advanced cancer patients with immune-cold tumor or relapsed from prior immunotherapies.

Presentation Details:

Abstract title: Early safety and efficacy from a phase I open-label clinical trial of CD137 (4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.
Abstract number: 2521
Poster Session: Developmental Therapeutics—Immunotherapy
The 2021 ASCO (Free ASCO Whitepaper) Annual Meeting will take place virtually on June 4 – 8, 2021 via the ASCO (Free ASCO Whitepaper) website, View Source

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About LVGN6051

LVGN6051 is xLinkAb anti-4-1BB (CD137) agonist mAb that has been designed to activate 4-1BB optimally in tumor microenvironment by targeting both 4-1BB and FcγRIIB. LVGN6051 strikes a balance between antitumor efficacy and safety by agonizing 4-1BB only in the presence of FcγRIIB, which is expressed on immune cells enriched in the tumor microenvironment, including B cells, dendritic cells and granulocytes.