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MIRATI THERAPEUTICS REPORTS INVESTIGATIONAL ADAGRASIB (MRTX849) PRELIMINARY DATA DEMONSTRATING TOLERABILITY AND DURABLE ANTI-TUMOR ACTIVITY AS WELL AS INITIAL MRTX1133 PRECLINICAL DATA

On October 25, 2020 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported preliminary results from the Company’s mutant KRAS selective inhibitor programs (Press release, Mirati, OCT 25, 2020, View Source [SID1234568956]). The preliminary results included updated clinical data of adagrasib (MRTX849), the Company’s KRAS G12C inhibitor, presented at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Therapeutics ("ENA") and initial preclinical in vivo data of MRTX1133, the Company’s selective and potent potential first-in-class KRAS G12D inhibitor.

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Adagrasib is a potent and selective inhibitor of KRAS G12C, optimized for a long half-life and a significant volume of tissue distribution to maintain continuous inhibition of KRAS-dependent signaling for the complete dose interval to maximize efficacy demonstrated by the depth and duration of anti-tumor activity.

"The adagrasib preliminary data presented today showed deep and durable anti-tumor activity in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other solid tumors, providing renewed hope for patients that harbor a KRAS G12C mutation. A 45% confirmed objective response rate for adagrasib as a monotherapy in advanced NSCLC is compelling. While this data is still maturing, adagrasib also demonstrated clinically meaningful duration of treatment for NSCLC patients in the Phase 1/1b cohort," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati. "Enrollment is complete in the Phase 2 cohort of adagrasib as a monotherapy treatment for patients in 2nd / 3rd line NSCLC and we anticipate submitting a New Drug Application for accelerated approval in the second half of 2021. Adagrasib has been well tolerated as a monotherapy and in combination with pembrolizumab, cetuximab and TNO-155, a SHP-2 inhibitor. We are initiating additional registration-enabling global clinical studies of adagrasib as both a monotherapy and in combinations as we expand the program to earlier lines of therapy in NSCLC and CRC."

Adagrasib tolerability at a dose of 600 mg BID in both monotherapy and combination trials:

In a pooled assessment of 110 patients harboring a G12C mutation in NSCLC, CRC and other solid tumors, monotherapy adagrasib has been well tolerated
4.5% of treatment-related adverse events led to discontinuation
Over 50 patients have been treated with adagrasib in combination with either pembrolizumab (a PD-1 inhibitor) in NSCLC, cetuximab (an anti-EGFR antibody) in CRC and TNO-155 (a SHP-2 inhibitor) in NSCLC or CRC
Each combination has been well tolerated
The pembrolizumab and cetuximab combination cohorts are ongoing and each have cleared the dose limiting toxicity evaluation period at the full dose of each commercial agent and at a 600 mg BID dose of adagrasib
The TNO-155 combination dose escalation and expansion cohorts are ongoing at a 600 mg BID dose of adagrasib
Preliminary efficacy data as of August 30, 2020 in patients with advanced NSCLC treated with adagrasib as a monotherapy at a 600 mg BID dose:

Patients had a median of two prior systemic treatments, including all patients receiving prior treatment with platinum-based chemotherapy regimens and 92% of patients receiving prior treatment with an anti-PD-1 /L1 inhibitor
Efficacy data from pooled Phase 1/1b cohort and Phase 2 registration-enabling cohort (n=51):
45% (23/51) confirmed objective response rate (ORR)
70% (16/23) of responders had a best tumor response greater than 40%
96% (49/51) disease control rate (DCR)
3.6 months median duration of follow-up
65% (33/51) of patients remain on treatment
83% (19/23) of responders have not progressed and remain on treatment
Efficacy data from the Phase 1/1b cohort (n=14):
43% (6/14) confirmed ORR
100% (14/14) DCR
8.2 months median duration of treatment
50% (7/14) of patients remain on treatment
83% (5/6) of responders remain in response and on treatment
4 of 6 responders have a duration of treatment for >11 months and all 4 patients remain on treatment
Preliminary explorative correlative analysis of co-mutations of KRAS G12C and STK11 in advanced NSCLC showed a 64% (9/14) ORR across pooled Phase 1/1b and Phase 2 cohorts:
Approximately 30% of all KRAS G12C mutant NSCLC patients have a STK11 co-occurring mutation
Co-occurring KRAS and STK11 mutations have been shown to be significantly correlated with poor clinical outcomes when treated with immunotherapy and platinum-based chemotherapy regimens
In a case study presented today from the ongoing clinical trial of adagrasib as a monotherapy, a heavily pre-treated NSCLC patient with an unirradiated, active brain metastases observed a 67% reduction in tumor volume including the disappearance of a metastatic brain lesion:
Preclinical studies demonstrate dose-dependent brain and cerebrospinal fluid (CSF) exposure
The Phase 2 cohort of adagrasib as a monotherapy is currently enrolling additional NSCLC patients with active brain metastases to further explore this patient population which has a high unmet medical need
In a case study presented today from the ongoing clinical trial of adagrasib in combination with TNO-155 (investigational SHP-2 inhibitor) in collaboration with Novartis, a heavily pre-treated NSCLC patient treated in the combination trial of adagrasib and TNO-155 (investigational SHP-2 inhibitor) observed a 60% reduction in tumor volume:

Data was from a scan on August 24, 2020
Prior therapy included treatment with a non-adagrasib monotherapy G12C direct inhibitor (with initial partial response followed by disease progression) and in combination with another SHP-2 inhibitor with chemotherapy (which was discontinued due to an adverse event)
Preliminary efficacy data as of August 30, 2020 in heavily pretreated patients with advanced CRC treated with adagrasib as a monotherapy at a 600 mg BID dose:

Median of 4 prior systemic treatments
Efficacy data from pooled Phase 1/1b and Phase 2 cohorts (n=18)17% (3/18) confirmed ORR with 2 of 3 responders remaining on treatment
94% (17/18) DCR
67% (12/18) of patients remain on treatment
55% (10/18) have a duration of treatment of >4 months
Preliminary efficacy data as of August 30, 2020 in patients with advanced solid tumors, other than NSCLC and CRC, treated with adagrasib as a monotherapy at 600 mg BID dose from a Phase 1/1b cohort:

One patient each (n=4) with pancreatic, ovarian, endometrial and cholangiocarcinoma tumors were treated, and each patient had a confirmed partial response to therapy
2 appendiceal cancer patients had stable disease
All 6 eligible patients remain on treatment
MRTX1133 Preclinical Summary

MRTX1133, the Company’s potent, selective and reversible inhibitor of KRAS G12D, binds to and inhibits mutant KRAS protein in both its active and inactive states. MRTX1133 exhibits single digit nanomolar potency and is >1000-fold selective for KRAS G12D compared with wild-type KRAS in cellular assays. Based on preclinical analyses, MRTX1133 has a projected human half-life exceeding 50 hours and exhibits a low propensity for drug interactions or off-target pharmacology. MRTX1133 demonstrated tumor regression in multiple in vivo tumor models, including pancreatic and colorectal cancers.

"MRTX1133, a potential first-in-class compound, continues to advance toward an Investigational New Drug filing in the first half of 2021. The drug properties and antitumor activity we’ve observed in preclinical tumor models continue to show promise," said James G. Christensen, Ph.D., Executive Vice President and Chief Scientific Officer at Mirati. "MRTX1133 has a low predicted target plasma concentration, based on its potency and high unbound fraction, and our goal is to achieve near complete and sustained target inhibition and maximal anti-tumor activity. To ensure sustained therapeutic levels are achieved, we are pursuing both oral and parenteral routes of administration in parallel as we plan for a Phase 1 clinical trial and intend to select the route that results in the optimal KRAS G12D inhibition. We are driven by the opportunity to positively impact the lives of patients with KRAS mutant cancers who have limited treatment options."

ENA Presentations on Adagrasib Clinical Data:

Pasi A. Janne, M.D., Ph.D., Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, Professor of Medicine, Harvard University and the Scientific Director of the Belfer Center for Applied Cancer Science, presented updated data for adagrasib in NSCLC patients from MRTX849-001. The presentation is titled, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation" (LBA-03).

Melissa L. Johnson, M.D., Associate Director of the Lung Cancer Research Program at Sarah Cannon Research Institute and Partner, Tennessee Oncology, PLLC, presented updated data for adagrasib in other solid tumors harboring a KRAS G12C mutation from MRTX849-001. The presentation is titled, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors Harboring a KRAS G12C Mutation" (LBA-04).

"It’s an inspiring and exciting time in the oncology field to see potential targeted therapeutic options for patients with the KRAS G12C mutation, a patient population that has historically faced limited treatment options. The clinical outcomes presented today, including the depth and maturing duration of responses in non-small cell lung cancer, colorectal cancers, and other solid tumors, along with the overall favorable safety profile, are highly encouraging," said Dr. Pasi Jänne.

Virtual Investor Event

Mirati will host a virtual investor event on October 25, 2020, at 1:30 p.m. PT/4:30 p.m. ET. Company executives will provide an overview of the adagrasib clinical data presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) conference and share initial preclinical data for MRTX1133, the Company’s KRAS G12D selective inhibitor.

Investors and the general public are invited to listen to a live webcast of the event through the "Investors" section of the Mirati corporate website at View Source Materials related to the webcast will be available at the same website prior to the event. A replay of the event will be available shortly after the conclusion of the event.

About Adagrasib (MRTX849)

Adagrasib is an investigational, orally available small molecule that is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are frequently linked to negative prognoses and are present in approximately 14% of non-small cell lung cancer (NSCLC) adenocarcinoma patients, 3-4% of colorectal cancer patients (CRC), and subsets of other types of cancer. Adagrasib is being evaluated as a monotherapy to treat patients with KRAS G12C-positive advanced solid tumors, including a registration enabling cohort in NSCLC. Adagrasib is also currently being evaluated in various combination cohorts in NSCLC and CRC with a PD-1 inhibitor, EGFR inhibitor, pan-EGFR inhibitor and SHP2 inhibitor.

About MRTX1133

MRTX1133 is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12D). MRTX1133 is in investigational new drug (IND)-enabling studies. KRAS G12D mutations impact an estimated 180,000 patients in the U.S. and Europe. The prevalence of the G12D oncogenic mutation is much higher than others including G12C, ALK, RET and TRK. G12D is present in approximately 36% of pancreatic patients, 12% of colorectal patients, 4% of NSCLC adenocarcinoma patients and 6% of endometrial patients.

Targeted inhibitor of mutated KRAS gene shows promise in early trial for lung, bowel, and other solid tumors

On October 25, 2020 Dana-Farber Cancer Institute reported A novel agent that targets a mutated form of the KRAS gene – the most commonly altered oncogene in human cancers and one long considered "undruggable" – shrank tumors in most patients in a clinical trial with manageable side effects, researchers reported at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Therapeutic, which is taking place online (Press release, Dana-Farber Cancer Institute, OCT 25, 2020, View Source;bowel–and-other-solid-tumors/ [SID1234568953]).

The KRYSTAL-1 (NCT03785249) phase I/II trial tested the agent, adagrasib (MRTX849), in patients with non-small lung cancer (NSCLC), colorectal cancer, and other solid tumors such as pancreatic, endometrial, and ovarian cancer. At today’s symposium, Pasi A. Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, reported that of 51 patients with NSCLC participating in the trial, 45% had an objective response, meaning their tumors shrank by 30% or more and did not grow or spread to other parts of the body. The disease control rate was 96%, meaning that 49 of the patients had a partial or complete response or stable disease.

Among the 14 patients in the phase I/Ib cohort who had been followed for a longer period of time (median time of 9.6 months), an objective response was seen in six (43%). Five of these six patients were still in ongoing treatment as of the cut-off date, with four of these six patients on the duration of treatment has lasted for more than 11 months.

Adagrasib targets a KRAS mutation called G12C, which is associated with a poor prognosis and lack of response to standard treatments. The mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC, 3-4% of colorectal cancers, and 2% of pancreatic cancers. This translates into well over 100,000 people each year worldwide.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its ability to send cell-growth signals and leading to cancer cell death.

Until recently no KRAS inhibitor had moved beyond preclinical testing, but in 2018 adagrasib was among several KRAS inhibitors approved by the U.S. Food and Drug Administration (FDA) for study in clinical trials beginning in January 2019. All patients in the KRYSTAL-1 phase I/II trial had advanced cancer and had previously received standard treatment for their disease, including chemotherapy and immunotherapy.

As part of the trial, researchers analyzed the treatment-related adverse side effects in all 110 patients who participated in the phase I/Ib and II parts of the trial, including those with colorectal cancer and other solid tumors, as well as those with NSCLC. Side effects included nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased levels of an enzyme that indicates minor liver irritation (20%). The only serious adverse side effect to occur in more than one patient was low sodium in the blood, which occurred in two patients.

"KRAS G12C patients are a population for which there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, treatment options are limited," said Jänne. "The fact that we are seeing responses in 45% of patients with adagrasib is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients."

Results for 31 trial participants with colorectal cancer or other solid tumors were presented by Melissa L. Johnson, MD, associate director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology.

Of 18 patients with colorectal cancer who could be evaluated, three (17%) had a confirmed objective response and two of them continue to receive treatment. Disease control was seen in 17 of the patients (94%) and 12 of these patients continue to be treated, including ten of 18 patients on treatment for greater than four months.

Among the six patients with other solid tumors who could be evaluated, a partial response was confirmed in one patient each with endometrial cancer, pancreatic cancer, ovarian cancer, and cancer of the bile duct (cholangiocarcinoma). Two appendiceal cancer patients who were treated achieved stable disease. All six patients remain on the treatment.

Researchers are also looking at combining adagrasib with other targeted therapies, such as pembrolizumab for NSCLC, cetuximab for colon cancer, investigational SHP-2 inhibitor, TNO-155, in either NCSLC or colon cancer and afatinib for NSCLC.

This study was sponsored by Mirati Therapeutics, Inc. Jänne is a compensated scientific advisor for Mirati Therapeutics.

Abstract no: 3 LBA, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation", by Pasi Jänne, presented in the Late Breaking and Best Proffered Papers Plenary session 2, channel 1, 15.45 hrs CET on Sunday 25 October:

View Source!abstractdetails/0000902150

Abstract no: 4 LBA, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors Harboring a KRAS G12C Mutation", by Melissa Johnson, presented in the Targeting Oncogenic RAS signalling: New Approaches To An Old Problem scientific session, Channel 2, 19.30 hrs CET on Sunday 25 October: View Source!abstractdetails/0000902140

ESSA Pharma Presents Therapeutic Potential of EPI-7386 at 32nd EORTC-NCI-AACR Symposium

On October 24, 2020 ESSA Pharma Inc. (Nasdaq: EPIX) (TSXV: EPI), a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported new preclinical data on ESSA’s clinical candidate, EPI-7386, at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Annual Symposium on Molecular Targets and Cancer Therapeutics ("ENA") (Press release, ESSA, OCT 24, 2020, View Source [SID1234568960]).

In an oral poster presentation titled, "The pre-clinical characterization of the N-terminal domain androgen receptor inhibitor, EPI-7386, for the treatment of prostate cancer", was published on Saturday, October 24th.

The studies highlight new information about EPI-7386 including:

In an in vitro cellular thermal shift assay (CETSA), EPI-7386 was shown to physically interact with the both the full-length and the splice variant (AR-V7) form of the androgen receptor ("AR").
In an in vitro full-length AR-driven cellular model (LNCaP), RNAseq data was analyzed by pathway enrichment analysis. EPI-7386 demonstrates largely similar modulation of AR-regulated genes compared to enzalutamide, but with additional unique elements.
EPI-7386 exhibits superior activity to enzalutamide in the AR-V7-driven cellular models LNCaP95 and 22Rv1 by modulating AR-driven gene expression with or without the addition of an external androgen.
"Previously, we presented in vitro data demonstrating that EPI-7386 binds to the full-length androgen receptor and can inhibit the transcription of AR-regulated genes. These new data demonstrate that EPI-7386 can also physically interact with the splice variant form, AR-V7, of the androgen receptor and inhibit its activity. The importance of this interaction with AR-V7 is seen through the superior transcriptional inhibition of AR-regulated genes by EPI-7386 compared to enzalutamide in the AR-V7-driven cell models LNCaP95 and 22Rv1. Together, these data provide important new insights into mechanistic aspects related to the binding and utility of EPI-7386 against AR-V7 splice-variant driven prostate cancer models. The data further strengthen the rationale for studying EPI-7386 in men with prostate cancer resistant to current anti-androgens." said Dr. David R. Parkinson, President and Chief Executive Officer.

Syros Presents Initial Data from Phase 1 Clinical Trial of SY-5609, Its Selective Oral CDK7 Inhibitor, at EORTC-NCI-AACR Meeting

On October 24, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported initial safety, pharmacokinetics (PK) and pharmacodynamics (PD) data from the ongoing dose-escalation portion of its Phase 1 clinical trial of SY-5609 in patients with select solid tumors (Press release, Syros Pharmaceuticals, OCT 24, 2020, View Source [SID1234568959]). SY-5609 is a highly selective and potent oral cyclin-dependent kinase 7 (CDK7) inhibitor. These early data demonstrate proof of mechanism in patients with advanced solid tumors and establish a maximum tolerated dose (MTD) for continuous daily dosing. The data are being presented in a poster session at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium.

"These early findings from our Phase 1 trial of SY-5609 reinforce our conviction in CDK7 inhibition as a potentially transformative targeted approach for difficult-to-treat cancers," said David A. Roth, M.D., Chief Medical Officer of Syros. "As we move forward in this trial, we are committed to fully exploring the potential of SY-5609. To that end, we opened the trial to pancreatic cancer patients, expanded a cohort to focus on lung cancer patients, and also expanded the combination cohort in treatment-resistant breast cancer patients. Additionally, we opened cohorts evaluating alternate dosing regimens, all with the goal of identifying optimal next steps for pursuing single-agent and combination development opportunities and ultimately delivering the greatest benefit to patients."

Early Data Demonstrate Proof-of-Mechanism at Tolerable Doses

Syros presented initial data from its ongoing Phase 1 multi-center, open-label, dose-escalation study of SY-5609 in patients with advanced breast, colorectal, lung, ovarian or pancreatic cancer, or other solid tumors with Rb pathway alterations. The study also includes a cohort evaluating SY-5609 in combination with fulvestrant in CDK4/6 inhibitor-resistant HR-positive breast cancer patients.

As of August 21, 17 patients had been enrolled in the trial and were eligible for safety, PK and PD analysis. Patients were either treated with continuous daily dosing of single-agent SY-5609 at 1, 3, 4 or 5 mg, or for three weeks on and one week off at 3 mg in combination with fulvestrant. The median age of the patients enrolled in the study was 64. Patients were heavily pretreated with a median of four prior therapies. The MTD for continuous daily dosing was achieved at 3 mg. The data showed that:

SY-5609 demonstrated dose-dependent increases in POLR2A mRNA expression, a PD marker being used in the trial to measure CDK7 biological activity.
Notably, increases in POLR2A in patients treated at 3 mg daily reached levels associated with tumor regressions in preclinical models, as well as with levels of CDK7 target engagement at which a clinical response and apoptosis were observed in a trial of patients treated with a first-generation IV CDK7 inhibitor.
SY-5609 demonstrated approximately dose-proportional PK as both a single agent and in combination, minimal accumulation with repeat dosing, and a steady state half-life compatible with once-daily dosing.
The majority of adverse events reported with SY-5609 as a single agent were low grade. The most common AEs were nausea, diarrhea, fatigue, platelet count decrease, and vomiting.
The safety profile of SY-5609 in combination with fulvestrant was consistent with that of single-agent SY-5609.
Five of the 13 patients treated with single-agent SY-5609 were response evaluable, and of those, three achieved stable disease and two had progressive disease; one of the four patients treated in the combination cohort was response evaluable and had progressive disease.
The Phase 1 trial continues to actively enroll patients with select solid tumors, including the recently expanded single-agent cohort in lung cancer patients and combination cohort in breast cancer patients, to further evaluate the 3 mg daily dose in focused patient populations. The trial has also been opened to patients with advanced pancreatic cancer, another tumor type that has demonstrated sensitivity to SY-5609 in preclinical models. Additional cohorts are evaluating alternate regimens, supported by preclinical data showing that intermittent regimens of SY-5609 induced tumor regressions.

Syros expects to report additional dose-escalation data, including clinical activity data, in mid-2021. Additional details about the Phase 1 trial of SY-5609 can be found using the identifier NCT04247126 at www.clinicaltrials.gov.

Turning Point Therapeutics Presents Initial Clinical Data From Phase 1 SHIELD-1 Study of Novel MET/SRC/CSF1R Inhibitor TPX-0022 at 2020 EORTC-NCI-AACR Symposium

On October 24, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported initial clinical data from the ongoing Phase 1 dose finding portion of its SHIELD-1 study of drug candidate, TPX-0022, a potent inhibitor of MET and the associated cancer signaling pathways of SRC and CSF1R (Press release, Turning Point Therapeutics, OCT 24, 2020, View Source [SID1234568955]). The initial data highlighted preliminary clinical activity, including objective responses across multiple tumor types and a generally tolerable safety profile.

The findings were reported in a late-breaking oral presentation by David Hong, M.D., Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center in the plenary session of the Molecular Targets and Cancer Therapeutics virtual symposium hosted by the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"Oncogenic alterations in MET – including exon 14 deletion, amplifications, fusions and activating kinase domain mutations – occur in many tumor types and patients continue to have limited available therapies," said Dr. Hong. "The initial data reported today for TPX-0022 is encouraging because it represents the potential for a new targeted therapy to improve the outcome in a wide range of MET-driven cancers."

TPX-0022, Phase 1 Initial Clinical Data
Twenty-two patients were treated across four dose levels from Sept. 2019 to the data cut-off date of Oct. 15, 2020. Patients included those with MET-altered non-small cell lung cancer (n=13), colorectal cancer (n=4), gastric or gastroesophageal (GE) junction cancer (n=4) and glioblastoma (n=1).

The median number of prior therapies was three (range 1 to 6), with all patients having received at least one prior line of chemotherapy and/or immunotherapy and the majority of patients having received multiple rounds of prior combination chemotherapy. Sixty-eight percent of patients had a baseline ECOG performance score of 1.

Preliminary efficacy data was available for 15 evaluable patients with baseline measurable disease and at least one post-baseline scan.

As of the 15 October 2020 data cut-off date:

Preliminary Safety and Pharmacokinetic (PK) Results (n=22)

A total of 22 patients with MET-dysregulated advanced solid tumors were treated with TPX-0022 at dose levels from 20 mg once daily (QD) to 120 mg QD.
TPX-0022 was generally well tolerated, with the most frequent treatment emergent adverse event (TEAE) being Grade 1 or 2 dizziness.
TEAEs reported in greater than 20 percent of patients were dizziness (55%); lipase increased (32%); fatigue (32%); amylase increased (27%); nausea (27%); vomiting (27%); constipation (23%); and anemia (23%).
The majority of treatment related adverse events (TRAEs) were Grade 1 or 2 and there were no Grade 4 or 5 TRAEs
The maximum tolerated dose had not been determined, with one dose-limiting toxicity of treatment-related Grade 2 dizziness at 120 mg QD.
PK data suggested sustained MET inhibition throughout the dosing interval across all doses.
Preliminary Efficacy Results (n=15)

A total of 15 patients were evaluable for efficacy by investigator assessment, including 10 who were MET TKI-naïve: four with colorectal cancer (CRC), three with non-small cell lung cancer (NSCLC), and three with gastric or GE junction cancer (GC or GEJ). In addition, five patients were MET TKI-pretreated, all with NSCLC.
Of 10 MET TKI-naïve patients, five achieved a partial response, including three with GC or GEJ cancer, one with CRC, and one with NSCLC. All three evaluable patients with gastric or GEJ tumors achieved a response.
Of the five responses, three patients achieved a confirmed response, and two patients remained on treatment in a response awaiting confirmation at the time of the data cut-off.
Of the five MET TKI-pretreated NSCLC patients, three patients treated with multiple rounds of prior therapy achieved a best response of stable disease with two patients showing tumor measurement improvements (-27%, and -75% accordingly).
Nine of 15 patients (9/15) achieved clinical benefit (confirmed and unconfirmed partial response or stable disease).
Six of 15 patients (6/15) remained on treatment with duration of treatment ranging from 7.6+ to 34+ weeks.
"We are encouraged by the emerging early safety and efficacy data across multiple tumor types, including the high unmet medical need area within MET-amplified gastric cancer where there are no approved targeted therapies," said Mohammad Hirmand, M.D., chief medical officer. "MET driven cancers affect a large and growing population of patients who have limited therapeutic options. Based on these early study findings, we look forward to advancing the development of TPX-0022."

The company anticipates initiating Phase 1 dose expansion after determining the recommended Phase 2 dose. Turning Point plans to discuss the ongoing Phase 1 SHIELD-1 study with the Food and Drug Administration (FDA) to potentially modify the trial into a registrational Phase 1/2 design. The company is targeting initiation of the Phase 2 portion in the second half of 2021, pending FDA feedback. In parallel, based on the SHIELD-1 study initial findings, a combination study with TPX-0022 and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with EGFR mutated MET-amplified NSCLC is also planned for initiation in the second half of 2021.

Repotrectinib Poster Presentations
In addition, preclinical data for the company’s lead drug candidate repotrectinib were reported in two poster presentations.

The first poster expanded on previous work presented in June at AACR (Free AACR Whitepaper) 2020 with additional preclinical data of repotrectinib in combination with the KRAS-G12C inhibitor, AMG-510, in a NSCLC xenograft tumor model. In preclinical studies, repotrectinib significantly enhanced efficacy of AMG-510 and showed a marked survival benefit in a KRAS G12C xenograft model when compared to AMG-510 alone.

Repotrectinib previously showed synergy in preclinical models with AMG-510 and inhibited KRAS G12C tumor cell proliferation, suppressed receptor tyrosine kinase upregulation induced by AMG-510, and reduced KRAS G12C tumor cell cytokine release. Similar results have since been obtained with other KRAS G12C inhibitors.

With the new results presented in a KRAS G12C xenograft tumor model, and previous data shown with repotrectinib in combination with a MEK inhibitor (presented at AACR (Free AACR Whitepaper) 2020), the company now plans to initiate a clinical combination study in KRAS mutant NSCLC in mid-2021. Further details on the design will be shared at the time of study initiation.

The second poster showed preclinical studies of repotrectinib as monotherapy and in combination with irinotecan and temozolomide in neuroblastoma cell lines and pediatric patient-derived xenograft (PDX) models. Repotrectinib combined with chemotherapy demonstrated increased anti-tumor activity compared to chemotherapy alone in an ALK-mutant neuroblastoma PDX model.

"With a growing body of supportive preclinical data, we are encouraged by the potentially broader role for repotrectinib across the treatment landscape," said Dr. Hirmand. "Repotrectinib’s inhibition of the cancer signaling pathways of SRC, FAK and JAK2, and its generally well-tolerated safety profile make it an ideal candidate for combination therapy. We look forward to advancing our combination strategy toward the initiation of clinical studies in 2021."

Webcast and Conference Call
Turning Point will host a webcast and conference call accompanied by a slide presentation to discuss the results from the SHIELD-1 Phase 1 study of TPX-0022 at 11:00 a.m. ET/8:00 a.m. PT today. Athena Countouriotis, M.D., president and chief executive officer, will host the call, which will also include Dr. Hirmand and Dr. Hong.

The discussion will be accessible through the "Investors" section of tptherapeutics.com or by dialing (877) 388-2118 (in the United States) or (470) 495-9489 (outside the U.S.) using conference ID 8655648. A replay will be available through the "Investors" section of www.tptherapeutics.com.