On June 4, 2021 Tachyon Therapeutics, Inc. ("Tachyon" or "the Company"), a research and development biotechnology company, reported two abstract presentations of the Company’s lead product candidate, TACH101, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Annual Meeting. ASCO (Free ASCO Whitepaper) is being held virtually from June 4-8, 2021 (Press release, Tachyon Therapeutics, JUN 4, 2021, View Source [SID1234583596]).

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"We are excited about the emerging preclinical profile of TACH101, the first inhibitor of KDM4 histone demethylase to be in clinical studies," stated Frank Perabo, MD, PhD, CEO of Tachyon Therapeutics. "Epigenetic processes play a fundamental role in regulation of cellular biology, but when unregulated, can lead to cancer development and progression. Data presented at ASCO (Free ASCO Whitepaper) show favorable pharmacologic properties for TACH101, compelling efficacy data in animal models, and broad applicability as a potential anti-cancer agent. We look forward to advancing this molecule into first-in-human trials later this year."

Highlights from the two ASCO (Free ASCO Whitepaper) abstracts are summarized below:

Abstract #3105

TACH101 demonstrated potent increase in H3 methylation levels (H3K36me3), showing on-target activity.
TACH101 triggered effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%.
Further evaluation using a panel of patient-derived colorectal models and patient-derived organoids showed a strong correlation of TACH101 sensitivity with MSI-H status (IC50 ranges 1-150 nM).
TACH101 reduced tumorigenic potential by 4.4-fold, suggesting that reduction of cancer stem cells by TACH101 may be effective in therapy-resistant settings.
The poster presentation of Abstract #3105 is available for viewing on the ASCO (Free ASCO Whitepaper) Annual Meeting website at View Source

Abstract #e15067

TACH101 showed potent KDM4 inhibition without significant off-target activity in in vitro and in vivo studies.
Pharmacokinetic studies showed TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog.
TACH101 had little or no inhibitory effects on CYP enzyme activities.
The exposure from oral administration in rats and dogs was dose proportional and was not affected by food intake in dogs.
Presentation of Abstract #e15067 is available for viewing on the ASCO (Free ASCO Whitepaper) Annual Meeting website at View Source

On June 4, 2021 Guardant Health, Inc. (Nasdaq: GH) reported that presents new data at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held from June 4-June 8, 2021, showing that its LUNAR-2 blood test is a highly sensitive test that can detect colorectal cancer (CRC) in early-stage cancer patients (Press release, Guardant Health, JUN 4, 2021, View Source [SID1234583594]). This largest ever cohort continues to demonstrate the performance and robustness of the LUNAR-2 assay.1,2

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Today, it is estimated that only 68% of adults, 50 years and older, are screened for CRC despite the Centers of Disease Control (CDC) target compliance goal of 80%.3-5 A patient-friendly blood testing option with high sensitivity could finally bridge the gap to this compliance goal, and bend the mortality curve for the second leading cause of cancer death in the U.S.6

The data (N=705) show that the LUNAR-2 assay achieved overall sensitivity of 91% in early-stage CRC (stage I, II, and III), and specificity of 94%. The performance in this new cohort of CRC cases, and cancer-free controls, is consistent with previously reported data.1-2 Notably, no differences in sensitivity for CRC detection were observed in patients presenting with asymptomatic disease, compared to those patients who were symptomatic, despite the lower cell-free DNA (cfDNA) tumor fractions observed in asymptomatic patients, suggesting the test will have clinically meaningful performance in an average-risk screening population. Further, an expanded multi-cohort analysis of over 1,300 cases of patients with CRC, demonstrated that the LUNAR-2 assay consistently delivers clinical meaningful sensitivity for the detection of early-stage cancer.

The LUNAR-2 assay achieves industry-leading performance for detecting early-stage CRC by simultaneously interrogating somatic, methylation, and fragmentomic signals from circulating tumor DNA (ctDNA) in the blood.

"It’s exciting to see the latest data on Guardant Health’s LUNAR-2 assay, which are consistent with prior data, but most importantly deliver the performance necessary for clinical adoption in average-risk colorectal cancer screening," said Jeeyun Lee, MD, Professor, Division of Hematology/Oncology, Samsung Medical Center. "It’s great to see the momentum Guardant Health has achieved since the introduction of their best-in-class liquid biopsy technology in 2014. Now, they are at the precipice of delivering a highly sensitive colorectal cancer screening test, and I look forward to seeing the outcome of their registrational study."

"What makes this data particularly exciting is that our LUNAR-2 assay continues to show clinically meaningful performance in increasingly larger cohorts of patients with early-stage cancer," said Helmy Eltoukhy, Guardant Health CEO. "Furthermore, our assay delivered comparable sensitivity in both asymptomatic and symptomatic patients, despite the significantly reduced signals in asymptomatic patients. We’re pleased with the test performance which exceeds the benchmark required for clinical adoption in an average-risk patient population."

The ECLIPSE trial, a 10,000-patient registrational study, is currently underway to evaluate the performance of LUNAR-2 to detect CRC in an average-risk adult population. If successful, Guardant Health expects data from the trial will support a premarket approval (PMA) submission to the FDA. The trial is expected to complete enrollment by the end of 2021.

On June 4, 2021 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that presented interim results from the Phase II SUMMIT basket trial, assessing the efficacy of neratinib in patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC), including patients with central nervous system (CNS) involvement, at the virtual 2021 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Puma Biotechnology, JUN 4, 2021, View Source [SID1234583593]). The presentation, entitled "Neratinib efficacy in a subgroup of patients with EGFR exon 18-mutant non-small cell lung cancer and central nervous system involvement: findings from the SUMMIT basket trial," is included in the Lung Cancer—Non-Small Cell Metastatic Poster Session (#9068).

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The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study that includes a cohort evaluating the safety and efficacy of neratinib administered daily to patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC). Patients received 240 mg of neratinib daily as a single agent with mandatory loperamide prophylaxis.

A cohort of 11 patients with EGFR exon 18-mutant NSCLC from the Phase II SUMMIT basket trial, including patients with central nervous system involvement, were evaluated for safety and efficacy. Prior lines of therapies included EGFR tyrosine kinase inhibitors (TKIs) (91%), chemotherapy (55%) and checkpoint inhibitors (IOs) (27%). Patients with stable, asymptomatic CNS metastasis were enrolled. Of the 11 patients, 3 patients had baseline CNS metastasis.

Of the 10 evaluable patients who had previously been treated with an EGFR tyrosine kinase inhibitor, 6 patients (60%) experienced a partial response (PR), and 4 patients (40%) demonstrated a confirmed partial response. Four additional patients showed stable disease (SD) lasting ≥16 weeks – bringing the experienced clinical benefit that includes confirmed complete response or partial response or stable disease for at least 16 weeks to 80%. The median duration of response (DOR) was 7.5 months, and the median progression-free survival (PFS) was 9.1 months with some patients remaining on treatment. Of the 3 patients who had CNS metastases, best responses were 2 PR and 1 SD and individual PFS times were 1.9 to 9.1 months. These results suggest that neratinib can be a potential treatment option for patients with NSCLC and hard-to-treat CNS metastases.

Neratinib was well tolerated in this study, with no occurrences of grade 3 diarrhea reported and there was no incident of any patient requiring a dose hold, dose reduction, hospitalization, or discontinuation of treatment due to diarrhea.

Jonathan W. Goldman, MD, Associate Professor of Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology at UCLA, an investigator on the trial, said, "EGFR exon 18-mutant lung cancer patients have no effective targeted options after first-line FDA-approved EGFR TKI therapy. This study shows that neratinib has the potential to be an efficacious and safe option to treat their disease, possibly with CNS activity as well."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "The descriptive findings from this study indicate that neratinib may have a role as a treatment option for rare cancers. We are excited to explore the full potential of neratinib and help patients with difficult to treat conditions."

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.