On April 27, 2020 I-SPY 2 TRIAL reported that results on April 27 at the clinical trial plenary session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 annual meeting, which showed that adding the immune checkpoint inhibitor durvalumab and the PARP inhibitor olaparib to standard of care pre-operative (neoadjuvant) chemotherapy improved outcomes for women with stage II/III, high-risk, HER2-Negative Breast Cancer (Press release, I-SPY 2 TRIAL, APR 27, 2020, View Source [SID1234556605]). Patients who received durvalumab + olaparib + paclitaxel (DOP) followed by doxorubicin/cyclophosphamide (AC), achieved complete eradication of their cancer from the breast and axillary lymph nodes at the time of surgery (i.e pathologic complete response) at a greater rate than patients treated with chemotherapy alone (37% versus 20%). This degree of response met the threshold for graduation, meaning that there is a greater than 85% predicted probability of success if this combination was tested against standard chemotherapy in a phase 3 trial of 300 neoadjuvant patients.

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I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. I-SPY 2 evaluates drugs (or combination of drugs) in parallel with the goal of determining which drugs work best in various types of breast cancer. I-SPY 2 patients are given chemotherapy before surgery so that response to treatment can be assessed. The primary endpoint of the study is pathologic complete response (pCR). Patients who participated in this study had tumors ≥ 2.5 cm, were HER2-negative, and if the cancer was hormone receptor positive (HR+) had to be classified as MammaPrint high risk status. Lead investigator of the study arm, Dr. Lajos Pusztai, Professor of Medicine and Director of Breast Cancer Translational Research at Yale Cancer Center, presented the efficacy and biomarker results which showed the predicted probability of pCR for the overall HER2-negative group, (22% vs 37%) and by subtypes, in HER2-negative/ER-positive (14% vs 28%) and triple negative (TNBC) (27% vs 47%) breast cancer subtypes.

The investigators also evaluated proposed potential markers that could identify the subgroup of patients who selectively benefited from the inclusion of immune enhancing agents such as durvalumab and DNA damage response targeting agents such as olaparib. Among the HR+/HER2- cohort, the MammaPrint ultra-high group was the primary beneficiary of the combined therapy (pCR rates 64% with the combination versus 22% with chemotherapy alone). Specific gene expression signatures thought to be associated with response were prospectively identified and the following were found to be associated with higher pCR in the experimental arm among TNBC: low CD3/CD8 ratio; high Macrophage/T cell-MHC class II ratio, and high proliferation. The safety signals were not unexpected. Adverse events were consistent with known side effects of these drugs. Overall 11% of patients in durvalumab + olaparib arm experienced immune-related grade 3 adverse events vs 1.3% in the control arm. According to Dr. Pusztai, chaperone for this arm in the I-SPY 2 TRIAL, "These results provide further evidence for the clinical value of immunotherapy in early stage breast cancer and suggest new avenues for how to exploit these drugs in HR+ breast cancers."

As noted by I-SPY 2 principal investigator, Dr. Laura Esserman of the University of California San Francisco, "There is a consistent signal of improved response from immuno-oncology and DNA damage response targeted agents in the adaptive I-SPY 2 platform trial as well as other trials, which gives us confidence that these types of agents will have a place in improving outcomes for women with highest risk early breast cancer. "

AACR has selected these findings as newsworthy and will be highlight during an AACR (Free AACR Whitepaper) webcast with the meeting program chair Dr. Antoni Ribas and AACR (Free AACR Whitepaper) President Dr. Elaine Mardis.

On April 27, 2020 GRAIL, Inc., a healthcare company whose mission is to detect cancer early, reported that new data for its investigational multi-cancer early detection blood test will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I (Press release, Grail, APR 27, 2020, View Source [SID1234556604]). These new data evaluate the performance of GRAIL’s test in symptomatic participants with suspicion of cancer.

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Today, the majority of deadly cancers do not have guideline-recommended screening tests available, and as a result, most cancers are detected too late, after they have progressed to late stages when chances of survival are much lower. There is also a high unmet need for early detection in the diagnostic assessment of symptomatic patients who are being evaluated for cancer. GRAIL’s multi-cancer early detection technology can detect more than 50 cancers, with a very low false positive rate of less than one percent, through a single blood draw. When a cancer signal is detected, the test can also identify where the cancer is located in the body (the tissue of origin) with high accuracy. This technology could be particularly useful in directing a more efficient diagnostic workup in symptomatic patients who are being evaluated for cancer.

"We continue to make significant progress in the validation of our multi-cancer early detection blood test, and wanted to assess its potential to drive efficiencies in the diagnostic workup of patients who are showing symptoms," said Alex Aravanis, MD, PhD, Chief Scientific Officer and Head of R&D, and a co-founder of GRAIL. "These findings show that when our multi-cancer test detected a cancer signal, it also identified where in the body that cancer was located with high accuracy. This is critical information for healthcare providers, and demonstrates the feasibility of our test to potentially accelerate diagnosis in individuals with high suspicion of cancer by helping direct the diagnostic workup."

These new data represent a pre-specified sub-group from GRAIL’s foundational Circulating Cell-free Genome Atlas (CCGA) study, which included more than 15,000 participants with or without a diagnosis of cancer. In the sub-group analysis reported at AACR (Free AACR Whitepaper), participants being evaluated for suspicion of cancer were classified as clinically confirmed cancer (n=164 in training, n=75 in validation) or clinically confirmed non-cancer (n=49 in training, n=15 in validation). In the confirmed non-cancer group, all training and validation samples were correctly predicted as non-cancer, or 100% specificity.

In the validation set, detection across all stages in the confirmed cancer group was 46.7% (n=35/75; 95% confidence interval [CI]: 35.1-58.6%) at 100% specificity. When renal cancers — which were overrepresented and subject to poor detection at early stages due to low tumor cfDNA fraction — were not included, detection across stages was 59.3% (n=35/59; 95% CI: 45.7-71.9%). In stages II and above, detection was 78.9% (n=30/38; 95% CI: 62.7-90.4%), all at 100% specificity. Performance was consistent across training and validation sets.

For cancers where a signal was detected, the tissue of origin (TOO) was predicted in 93.9% (n=62/66) of samples in training, and 100% (n=35/35) in validation. Of those with a TOO result, accuracy was 85.5% (n=53/62; 95% CI: 74.2-93.1%) and 97.1% (n=34/35; 95% CI: 85.1-99.9%), respectively.

The data are being presented online by David D. Thiel, MD, Chair, Mayo Clinic Florida Department of Urology. The presentation slides will be available at View Source after the presentation.

AACR Presentation Details

Abstract CT291
Lincoln Nadauld, et al. The PATHFINDER Study: Assessment of the implementation of an investigational multi-cancer early detection test into clinical practice
Session VPO.CT07.03 – Phase III Trials in Progress: April 27, 2020: 9:00AM-6:00PM EDT

Abstract CT021
David D. Thiel, et al. Prediction of cancer and tissue of origin in individuals with suspicion of cancer using a cell-free DNA multi-cancer early detection test
Session VCTPL02 – Early Detection and ctDNA: April 28, 2020: 1:40PM-1:50PM EDT

About CCGA

The Circulating Cell-free Genome Atlas (CCGA) study is a prospectively designed, observational, longitudinal, case-control study that has completed enrollment of approximately 15,000 participants with and without cancer across 142 sites in the United States and Canada. CCGA is designed to characterize the landscape of genomic cancer signals in the blood, and to discover, train, and validate GRAIL’s multi-cancer early detection blood test through three pre-planned sub-studies. To learn more about CCGA, please visit www.grail.com.

About GRAIL’s Multi-Cancer Early Detection Test

GRAIL’s multi-cancer early detection test is designed to detect cancers in early stages, when the chance of survival is higher than if cancer is detected after symptoms appear. Clinical data have shown the ability of this technology to detect more than 50 cancer types with a very low false positive rate of less than one percent. GRAIL’s test was designed to minimize false positives in order to limit associated harms, including patient anxiety and unnecessary diagnostic workups. When a cancer signal is detected, the test has been able to identify where in the body the cancer is located with high accuracy, an important step to guiding diagnostic next steps and care.

GRAIL’s methylation-based technology preferentially targets the most informative regions of the genome and is designed to use its proprietary database and machine-learning algorithms to both detect the presence of cancer and identify the tumor’s tissue of origin. GRAIL believes its sequencing database of cancer and non-cancer methylation signatures is the largest of its kind.

On April 27, 2020 Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to developing and commercializing new medicines for patients battling cancer, reported results from the ongoing investigator-initiated Phase 1 clinical study investigating VS-6766, its RAF/MEK inhibitor, in combination with defactinib, its FAK inhibitor, in patients with KRAS mutant advanced solid tumors (Press release, Verastem, APR 27, 2020, View Source [SID1234556603]). The data will be presented as a virtual poster today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting I.

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This ongoing study is an open label, dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with advanced solid tumors, including low-grade serous ovarian cancer (LGSOC), KRAS mutant non-small cell lung cancer (NSCLC) and KRAS mutant colorectal cancer (CRC). In the LGSOC cohort, among the patients with KRAS mutant tumors (n=6), 4 patients responded, for an overall response rate (ORR) of 67%. Median time on treatment was 20.5 months. In the KRAS mutant NSCLC cohort (n=10), 1 patient achieved a partial response and 8 patients achieved disease control. In this cohort, 70% of patients continued on treatment at least 12 weeks and 30% of patients continued on treatment at least 24 weeks.

Based on an observation of higher response rates seen in patients with KRASG12V mutations in the investigator-initiated Phase 1 combination study, we conducted a combined analysis with data from the combination study and the prior single-agent study that utilized a twice-weekly dosing schedule of VS-67661 to get a more complete picture of activity in KRASG12V mutations. The subsequent, combined analysis (VS-6766 monotherapy and defactinib combination) showed a 57% ORR (4/7 patients); as a single agent (2/5 patients) and in combination with defactinib (2/2 patients) in KRASG12V mutant NSCLC. Similarly, the combined analysis showed a 60% ORR (3/5 patients); as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRASG12V mutant gynecologic cancers. These additional analyses were conducted by Verastem Oncology to understand the impact that various KRAS variants may have had on response to identify potential signals to pursue in future prospective studies. This additional analysis was not part of the AACR (Free AACR Whitepaper) 2020 poster presentation.

"Earlier research has demonstrated MEK inhibitors can cause upregulation of FAK in KRAS mutant tumors, which are notoriously difficult to treat and quite common across solid tumors. The combination of a RAF/MEK and FAK inhibitor can potentially overcome this challenge and opens up an exciting new pathway for treatment," stated Professor Udai Banerji, Professor of Molecular Cancer Pharmacology at The Institute of Cancer Research, London, and Honorary Consultant in Medical Oncology, MBBS, MD, DNB, PhD, FRCP at The Royal Marsden NHS Foundation Trust, London, and lead investigator of the clinical study. "We found that the combination of VS-6766 and defactinib in low-grade serous ovarian cancer (LGSOC) was well tolerated by the patients in the trial and shows promising clinical activity, including durable response that is associated with clinically meaningful benefit. The study continues to enroll additional patients into the ovarian, lung and colorectal expansion cohorts with additional responses seen in all cohorts."

"We are encouraged by these early response rates in KRAS mutant LGSOC and in KRASG12V mutant tumors as they underscore the significant potential of this novel approach in areas of high unmet medical need," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "The potential of the combination of VS-6766 and defactinib is rapidly evolving as we continue to gain more insights and analyze the data. We plan to initiate discussions with regulatory authorities as soon as possible to define a path forward, with the goal of commencing a registration-directed clinical trial during 2020."

Initial Results from the Phase 1 Study Investigating the Combination of VS-6766 and Defactinib in Patients with KRAS Mutant Cancers and Subsequent Analyses

The poster presentation describes safety and dose response data from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated Phase 1 study conducted in the United Kingdom assessing the combination of RAF/MEK and FAK inhibitor therapy in patients with LGSOC and KRAS mutant NSCLC. The study evaluated the combination of VS-6766 and defactinib. VS-6766 was administered using a twice-weekly dose escalation schedule and was administered 3 out of every 4 weeks. Defactinib was administered using a twice-daily dose escalation schedule, also 3 out of every 4 weeks. Dose levels were assessed in 3 cohorts: cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg, defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib 400mg).

In the patients with LGSOC (n=8), the ORR was 50% (n=4). Among the patients with KRAS mutant LGSOC (n=6), the ORR was 67% (n=4). Of the 4 patients who have responded, 3 had a prior MEK inhibitor and as of November 2019 had been on study for a median of 20.5 months (range 7-23 months). In the patients with NSCLC (n=10), all of which had KRAS mutations, 1 patient achieved a partial response and 1 patient with a 22% tumor reduction still on treatment as of November 2019. Median time on treatment for this cohort was approximately 18 weeks.

Based on an observation of higher response rates seen in patients with KRASG12V mutations in the investigator-initiated Phase 1 combination study, we conducted a combined analysis with data from the combination study and the prior single-agent study that utilized a twice-weekly dosing schedule of VS-67661 to get a more complete picture of activity in KRASG12V mutations. The subsequent, combined analysis (VS-6766 monotherapy and defactinib combination) showed a 57% ORR (4/7 patients); as a single agent (2/5 patients) and in combination with defactinib (2/2 patients) in KRASG12V mutant NSCLC. Similarly, the combined analysis showed a 60% ORR (3/5 patients); as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRASG12V mutant gynecologic cancers. These additional analyses were conducted by Verastem Oncology to understand the impact that various KRAS variants may have had on response to identify potential signals to pursue in future prospective studies. This additional analysis was not part of the AACR (Free AACR Whitepaper) 2020 poster presentation.

The most common side effects seen in the Phase 1 study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC Grade 1/2 and all were reversible. The recommended Phase 2 dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).

The preliminary data reported in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRASmutant LGSOC and KRASG12V mutant NSCLC, including patients previously treated with a MEK inhibitor. Expansion cohorts remain ongoing.

Details for the AACR (Free AACR Whitepaper) 2020 Virtual Meeting I presentation are as follows:

Title: Phase 1 study of the combination of a RAF-MEK inhibitor CH5126766 (VS-6766) and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers
Lead author: Udai Banerji, The Institute of Cancer Research and The Royal Marsden
Poster #: CT143
Session: VPO.CT01 – Phase I Clinical Trials
Date and Time: Monday, April 27, 2020; 9:00 a.m. to 6:00 p.m. ET
URL: View Source!/9045/presentation/10642

Conference Call and Webcast Information

The Verastem Oncology management team will host a conference call and webcast on Monday, April 27, 2020, at 8:00 AM ET to discuss the Phase 1 RAF/MEK/FAK combination data. The call can be accessed by dialing (877) 341-5660 (U.S. and Canada) or (315) 625-3226 (international), five minutes prior to the start of the call and providing the passcode 8390795.

The live, listen-only webcast of the conference call can be accessed by visiting the investors section of the Company’s website at www.verastem.com. A replay of the webcast will be archived on the Company’s website for 90 days following the call.

About VS-6766

VS-6766 (formerly known as CH5126766, CKI27 and RO5126766) is a unique inhibitor of the RAF/MEK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and the focal adhesion kinase (FAK) inhibitor defactinib is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).2 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC3 and VS-6766 in KRAS mutant NSCLC and LGSOC.1

About Defactinib

Defactinib is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors. The Company has received Orphan Drug designation for defactinib in ovarian cancer and mesothelioma in the US, EU and Australia. Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.4,5 Additionally, in both preclinical and clinical studies, FAK activation has been shown to occur as a potential resistance mechanism in response to MEK inhibitor treatment, and synergy of a FAK inhibitor with a RAF/MEK inhibitor has been shown in several preclinical models. The combination of defactinib and VS-6766 is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).2 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC3 and VS-6766 in KRAS mutant NSCLC and LGSOC.4 Defactinib is also in clinical testing in combination with pembrolizumab for treatment of patients with pancreatic cancer, NSCLC and mesothelioma.6

On April 26, 2020 The University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division and Ipsen Biopharmaceuticals reported the preclinical discovery and early-stage clinical development of this novel drug (Press release, MD Anderson, APR 26, 2020, View Source [SID1234556628]). IPN60090, now under investigation in a Phase I trial, may hold benefit for certain patients with lung and ovarian cancers.

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MD Anderson’s GLS1 program was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within Therapeutics Discovery. Development of the program continues in collaboration with Ipsen, which licensed the therapeutic in 2018.

Findings and information about the ongoing trial will be presented today at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I by Jeffrey Kovacs, Ph.D., institute group leader with TRACTION and co-leader of the GLS1 program.

"This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine," said Kovacs. "Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials."

Dysregulation of cellular metabolism is a hallmark of cancer development, and the GLS1 enzyme plays a key role in many metabolic processes. Thus, it makes an attractive target for cancer therapy, explained Kovacs.

IACS drug-discovery scientists identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, and translational researchers in TRACTION demonstrated its activity against subsets of lung and ovarian cancer preclinical models.

Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in the KEAP1 and NFE2L2 genes, which regulate response to oxidative stress, sensitize cells to treatment with IPN60090. Similarly, low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers predicts response to IPN60090 in preclinical models.

"Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we’re able to offer patients the most relevant therapies," said Timothy A. Yap, M.B.B.S., Ph.D., F.R.C.P., associate professor of Investigational Cancer Therapeutics and medical director of IACS. "These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options."

For example, patients with lung cancers harboring KEAP1/NRF2 mutations have not benefited from treatment with immune checkpoint inhibitors and have poorer outcomes overall, explained Yap, who leads the IPN60090 clinical trial at MD Anderson.

IPN60090 currently is under investigation in a Phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that harbor KEAP1/NFE2L2 mutations or have low ASNS levels. The team has developed novel CLIA-certified assays to identify patients likely to benefit and monitor how effectively the drug is acting. Initial data from the clinical trial indicate that IPN60090 is effectively inhibiting GLS1 activity in peripheral blood mononuclear cells from patients.

Future trial cohorts plan to investigate IPN60090 in combination with checkpoint inhibitors, chemotherapy and targeted therapies identified by the researchers as having potential synergistic benefits with GLS1 inhibition.

The ongoing research is supported by Ipsen through a global licensing and development agreement. The research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. Kovacs is a co-inventor on material and method-of-use patent applications related to IPN60090. The Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program.

On April 26, 2020 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported the submission of a New Drug Application (NDA) to the Ministry of Health, Labour and Welfare (MHLW) by Janssen Pharmaceutical K.K. (Janssen) seeking approval of a new subcutaneous (SC) formulation of daratumumab, an intravenous (IV) treatment approved for patients with multiple myeloma (Press release, Halozyme, APR 26, 2020, View Source [SID1234556601]).

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"We are pleased to see this New Drug Application submission in Japan, which builds on Janssen’s prior regulatory submissions in the U.S. and EU that are currently under review," said Dr. Helen Torley, president and chief executive officer. "We are excited that patients with multiple myeloma in Japan may soon have a new therapeutic option that can be administered with a shorter infusion time when compared with a multi-hour intravenous infusion."

The NDA is supported by pivotal data from the Phase 3 COLUMBA (MMY3012) study – a randomized open label study – that included a non-inferiority comparison of daratumumab SC formulation versus daratumumab IV administration in patients with multiple myeloma who had received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease was refractory to both PI and IMiD. In addition to non-inferiority, daratumumab SC showed a lower rate of infusion-related reactions. Data from the Phase 2 PLEIADES (MMY2040) study – a non-randomized open label study conducted in newly diagnosed or relapsed or refractory multiple myeloma patients – are also included in the NDA. The subcutaneous formulation of daratumumab is co-formulated with Halozyme’s ENHANZE drug delivery technology, based on recombinant human hyaluronidase PH20 (rHuPH20).

About ENHANZE Technology
Halozyme’s proprietary ENHANZE drug delivery technology is based on its patented recombinant human hyaluronidase enzyme (rHuPH20). rHuPH20 has been shown to remove traditional limitations on the volume of biologics that can be delivered subcutaneously (just under the skin). By using rHuPH20, some biologics and compounds that are administered intravenously may instead be delivered subcutaneously. ENHANZE may also benefit subcutaneous biologics by reducing the need for multiple injections. This delivery has been shown in studies to reduce health care practitioner time required for administration and shorten time for drug administration.