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Turning Point Therapeutics’ Lead Drug Candidate Repotrectinib Increases Effectiveness of KRAS-G12C and MEK Inhibitors in Preclincal KRAS Cancer Models

On June 22, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported preclinical studies highlighting the potential for its lead drug candidate, repotrectinib, to increase the effectiveness of KRAS-G12C and MEK inhibitors in cancer models, and for its next-generation ALK inhibitor candidate, TPX-0131, to overcome ALK-resistant mutations (Press release, Turning Point Therapeutics, JUN 22, 2020, View Source [SID1234564369]).

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The studies were included as part of three poster presentations at today’s virtual annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"Feedback reactivation and bypass signaling may limit the efficacy of KRAS-G12C and MEK inhibitors against KRAS-driven tumors, and our encouraging preclinical data shows how repotrectinib has the potential to increase the anti-tumor effects by inhibiting SRC, FAK and JAK2 signaling," said Athena Countouriotis, M.D., president and chief executive officer. "We look forward to building upon these preclinical combination studies as we explore the potential for repotrectinib to address a broad set of oncogenic-driven solid tumors.

"In addition, we are excited to share for the first time preclinical data for our fourth drug candidate, TPX-0131, a next generation ALK inhibitor in IND enabling studies. We are encouraged by TPX-0131’s preclinical potency against both wildtype ALK and the most common resistant mutations."

Jessica Lin, M.D., Attending Physician in the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center and Henri and Belinda Termeer Center for Targeted Therapies, and Instructor in Medicine at Harvard Medical School said: "Resistant mutations following treatment with approved ALK inhibitors remain a challenge for patients, especially the difficult to treat G1202R/del solvent front mutation which can occur in up to 42 percent of patients who develop a resistance mutation, and compound mutations that develop after the recently approved agent Lorbrena. The preclinical potency of TPX-0131 against these mutations suggests that it warrants further study."

Repotrectinib Combination Studies
The preclinical antitumor activities of repotrectinib in combination with proxy molecules for AMG510, an investigational KRAS-G12C inhibitor, and trametinib, an approved MEK inhibitor were highlighted for the first time in two poster presentations. The studies show repotrectinib’s inhibition of SRC, FAK and JAK2 at therapeutically relevant concentrations, which in combination with AMG510 or trametinib demonstrated a synergistic effect over the single agent by reducing tumor cell growth and enhancing tumor cell death. The repotrectinib-trametinib combination studies were replicated across panels of KRAS mutant non-small cell lung, colorectal and pancreatic cancer cell lines that harbor a spectrum of KRAS mutations.

The frequently mutated Kirsten Rat Sarcoma (KRAS) viral oncogene is associated with a broad range of human cancers, including approximately 25 percent of non-small cell lung, 45 percent of colorectal and 75 percent of pancreatic cancers. Therapeutic targeting of KRAS has proven challenging, in part due to resistance and adaptive upregulation of alternative signaling pathways that promote tumor cell survival, as well as concurrent secretion of various cytokines and growth factors.

In preclinical models, repotrectinib inhibits SRC and FAK signaling, a key pathway for oncogenic resistance, and JAK2, a driver of cytokine secretion pathways.

TPX-0131, a Next-Generation ALK Inhibitor
TPX-0131 has been internally designed with a compact macrocyclic structure to bind completely within the ATP binding site of ALK. In preclinical studies, TPX-0131 potently inhibits wildtype ALK and numerous ALK mutations, in particular the clinically observed G1202R solvent-front mutation and G1202R/L1196M compound mutation.

In cell proliferation assays presented at AACR (Free AACR Whitepaper), TPX-0131 exhibited greater potency against wildtype ALK as compared to proxy molecules for approved front-line ALK inhibitors crizotinib, alectinib, brigatinib and ceritinib, and comparable potency to a proxy molecule for approved ALK inhibitor, lorlatinib. TPX-0131 demonstrated more than 100-fold greater potency against the G1202R solvent-front mutation as compared to proxy molecules for the approved ALK inhibitors. Additionally, TPX-0131 is the most potent inhibitor against a range of EML4-ALK compound mutations while prior generation ALK inhibitors tested have shown moderate to no activity.

Anaplastic lymphoma kinase- (ALK) driven tumors are estimated to represent up to 7 percent of driver oncogenes in non-small cell lung cancer and in one study of patients who develop a resistance mutation, G1202R was reported in approximately 42 percent of patients, and compound mutations have been reported in approximately 35 percent of patients who developed resistance following treatment with lorlatinib.

The three posters presented today are:

Title: Repotrectinib increases effectiveness of KRAS-G12C inhibitors in KRAS-G12C mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1958

Title: Repotrectinib increases effectiveness of MEK inhibitor trametinib in KRAS mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1957

Title: TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitorsbstract Number: 5226

Targovax to present at the upcoming 2020 Virtual European Biotech Investor Day 2020

On June 22, 2020 Targovax ASA, a clinical stage immuno-oncology company developing oncolytic viruses to target hard-to-treat solid tumors, reported that Magnus Jäderberg, Chief Medical Officer of Targovax, will present an overview of the company at the upcoming Virtual European Biotech Investor Day 2020 hosted by Solebury Trout, Goodwin, Deutsche Bank and Nasdaq (Press release, Targovax, JUN 22, 2020, View Source [SID1234564003]).

Participants will be able to submit questions electronically during the presentation, with answers provided at the discretion of the company on an individual basis afterwards.

Details are as follows:
Date/Time: Thursday June 25, at 5:30 pm CET / 11:30 am EDT
To access the presentation, please login here.
Archive of the event will be available on the Company’s website at www.targovax.com.

Targovax’s ONCOS-102 mesothelioma 12-month data powerfully demonstrate broad immune activation linked to clinical benefit

On June 22, 2020 Targovax ASA (OSE: TRVX), a clinical stage immuno-oncology company developing oncolytic viruses to target hard-to-treat solid tumors, reported 12-month efficacy and immunological data from the randomized phase I/II trial of ONCOS-102 in combination with standard of care chemotherapy in malignant pleural mesothelioma (MPM) (Press release, Targovax, JUN 22, 2020, View Source [SID1234564002]).

The trial is an open label, exploratory phase I/II trial adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and second (and later) line MPM to assess safety, immune activation and clinical efficacy vs SoC only. In total, 31 patients have been treated in the trial, with 20 patients in the experimental group receiving the ONCOS-102 and SoC combination, and 11 patients in a control group receiving SoC only. The 31 patients have now completed the 12-month follow-up. The first set of data was reported in January 2020, see press release here, with an update in May 2020, see press release here.

The median Progression Free Survival (mPFS) for ONCOS-102 treated first line patients remains at 8.9 months, which is identical to the previously reported early data. mPFS for the control group first line patients treated with SoC chemotherapy only is 7.6 months. The first line mPFS data continues to compare favorably to SoC historical controls, which have shown mPFS of 5.7-7.3 months[1]. As there is now longer follow-up and few censored patients left in the PFS analysis, the updated figures can be considered close to final.

The 12-month survival rate was 64% in the first line ONCOS-102 treated patients, compared to 50% in the first line control group treated with SoC chemotherapy only (median Overall Survival is too early to report). The patients continue to be followed and updated Overall Survival (OS) figures will be published as they mature. This 64% 12-month survival rate is encouraging compared to the control group, but there are few historical control reference points. Recently, at ASCO (Free ASCO Whitepaper) 2020, results from a first line mesothelioma trial assessing SoC chemotherapy in combination with the anti-PD-L1 checkpoint inhibitor durvalumab showed a 70% 12-month survival rate. This suggests that ONCOS-102 alone plus SoC chemotherapy may already achieve a level of benefit close to that observed with checkpoint inhibition plus SoC chemotherapy. It is expected that addition of checkpoint inhibition to ONCOS-102 and Soc will provide even further clinical benefit due to engagement of distinct and complementary biological mechanisms. As such, Targovax’s future clinical development of ONCOS-102 will focus on first line mesothelioma with the triple combination of a checkpoint inhibitor, ONCOS-102 and SoC. A randomized phase II trial is currently being planned in collaboration with a pharma partner.

Tumor biopsy immunohistochemistry and gene expression analyses from the present trial confirm the predicted mode of action of ONCOS-102. Importantly, profound innate and adaptive immune activation is observed in the ONCOS-102 treated patients compared to the control group, and this immune activation is associated with better clinical outcome. The immune activation is hallmarked by an increase in intra-tumoral cytotoxic T-cells and upregulation of adaptive immunity and cytotoxicity related gene expression, in parallel with polarization from M2 to M1 macrophage phenotype and upregulation of PD-L1 expression, indicating that ONCOS-102 is driving a favorable remodeling of the tumor microenvironment. This powerfully demonstrates the immune activation potential of ONCOS-102 far beyond what is achieved by chemotherapy alone and suggests that patients may be effectively sensitized to treatment with an anti-PD1/L1 antagonist, thereby providing strong scientific rationale for the combination of ONCOS-102 and checkpoint inhibition in first line mesothelioma.

Dr. Magnus Jäderberg, Chief Medical Officer of Targovax, said: "We are very pleased to see the encouraging first line PFS data holding up in the 12-month analysis, with early signs of positive survival outcomes. We are particularly excited to observe a broad and profound immune activation in the ONCOS-102 treated patients, which confirms the proposed mode of action. ONCOS-102 treatment clearly drives a favorable remodeling of the tumor microenvironment, and this remodeling is linked to better clinical outcomes. This immune activated tumor micro-environment provides the key scientific rationale and an ideal backdrop for combination treatment with a checkpoint inhibitor. These data set us up perfectly to move forward with a trial combining ONCOS-102 and a checkpoint inhibitor, which we believe will release the full potential of immunotherapy in this hard-to-treat patient population".

Roche, BioNTech post ‘low’ response rate in cancer vaccine trial

On June 22, 2020 BioNTech reported that A phase 1b trial of a personalized cancer vaccine in development at Roche has chalked up a "low" response rate (Press release, BioNTech, JUN 22, 2020, View Source [SID1234561516]). Nine of the 108 evaluable solid tumor patients responded when given the vaccine in combination with Tecentriq, although researchers pointed to immune response results to support continued study in other populations.

Roche’s Genentech paid BioNTech $310 million in upfront and near-term milestones in 2016 to gain access to mRNA-based personalized cancer vaccines. The collaboration gave rise to RO7198457, a drug that targets up to 20 tumor-associated antigens (TAAs) expressed by a patient’s cancer. By giving patients mRNA corresponding to TAAs, Roche and BioNTech hope to rally cytotoxic T-lymphocyte and memory T-cell-dependent immune responses against tumors.

Researchers are using this week’s virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) event to share an early look at whether RO7198457, also known as BNT122, works as hoped. The results contain plenty of ammunition for anyone who is skeptical about the likelihood of Roche and BioNTech ending the long losing streak of cancer vaccines.

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Evaluations of 108 patients who received RO7198457 and checkpoint inhibitor Tecentriq identified nine responses, including one complete response. The figures translate into a response rate of 8%. It is unclear whether those subjects would have responded to Tecentriq given as a monotherapy. A smaller assessment of RO7198457 as a monotherapy linked the cancer vaccine to a 4% response rate.

Juanita Lopez, Ph.D., consultant medical oncologist at The Royal Marsden and co-author of the RO7198457 abstract, said the "clinical response rate overall was low" in a statement about the trial. Despite that, Lopez sees positives in the results, noting that "we were able to generate tumor-specific immune responses in the majority of evaluable patients."

An analysis of peripheral blood taken from 49 patients found evidence of neoantigen-specific T cell responses in 77% of samples. Viewed alongside the efficacy data, the analysis suggests RO7198457 reliably elicits specific immune responses that rarely translate into reductions in tumor size.

Lopez thinks the health status of participants at baseline may explain why immune activity is failing to translate into partial and complete responses. Participants in the combination trial had received a median of three prior therapies. Almost 40% of subjects had previously received immunotherapy. It is unclear if any of the nine patients who responded to the combination had previously received an immunotherapy.

The debate over whether RO7198457 is a dud or a good drug given to the wrong patients will remain inconclusive until data from other populations are available. Roche and BioNTech began gathering such data last year by initiating a phase 2 trial of RO7198457 in combination with Merck’s Keytruda. The trial is randomizing previously untreated advanced melanoma patients to receive Keytruda as a single agent or in combination with RO7198457.

That design positions the trial to clear up questions raised by the Tecentriq combination study about what RO7198457 contributes to checkpoint inhibitor cocktails and whether it works better earlier in the treatment pathway. Lopez said work to assess RO7198457 in post-surgery early-stage non-small cell lung cancer patients is also underway.

Biomarker Test Highly Accurate in Detecting Early Kidney Cancer

On June 22, 2020 Dana-Farber Cancer Institute reported that a novel liquid biopsy method can detect kidney cancers with high accuracy, including small, localized tumors which are often curable but for which no early detection method exists (Press release, Dana-Farber Cancer Institute, JUN 22, 2020, View Source [SID1234561515]).

The report in Nature Medicine suggests that if validated in larger trials and applied widely, the non-invasive test could find more early kidney cancers when they haven’t spread, thus reducing the mortality of the disease. "Hopefully we can scale this to a much larger level and detect cancer earlier so we can act earlier," said Toni Choueiri, MD, a co-senior author of the study. He is the director of the Lank Center for Genitourinary Oncology at Dana-Farber.

It’s estimated that 73,750 new kidney cancer cases will be diagnosed in 2020, and about 14,830 will die of the disease. About 35 percent of cancers are diagnosed only after they have spread beyond the kidney and are more difficult to treat. Small, early kidney tumors usually cause no symptoms, and increasingly are found incidentally in scans of the abdomen performed for another purpose. However, there is no imaging or other screening test recommended for the general population to look for early kidney cancers. Initially, a test based on the method described in the new report might be used to screen people with a family history of kidney cancer, or who had a previous kidney cancer, said Choueiri. "We need to be specific first, before making it totally mainstream," he said.

Non-invasive liquid biopsies, which search for cancer-related DNA shed by tumors into blood or other body fluids, are moving rapidly toward clinical use as a means of early detection for some kinds of tumors. However, "kidney cancer is one of the hardest tumors to detect, because it doesn’t shed as much DNA as other tumors," said Matthew Freedman, MD, a medical oncologist at Dana-Farber and co-senior author of the report. "That’s where this test performs really well" because it can identify abnormal patterns in small amounts of tumor-shed DNA. "And it’s a proof of principle that early stage disease is detectable."

The test was nearly 100 percent accurate when used with blood samples to distinguish patients with kidney cancer from those known to be free of kidney cancer. The method achieves less accuracy in testing urine samples, but the researchers believe that performance can be improved. If the test is validated in larger trials and becomes widely applicable clinically, a urine sample would be even less-invasive than a blood draw.

The technical name for the testing method is cfMeDIP-seq, which stands for cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Where other liquid biopsy methods search for mutations in tumor-shed DNA that reveal the type and location of cancer, cfMeDIP-seq detects abnormal methylation – the addition of chemical tags to DNA, which doesn’t alter their genetic code but can affect their function.

The method was tested on samples from 99 patients with early and advanced kidney cancer, 15 patients with stage IV urothelial bladder cancer, and 28 healthy, cancer-free control subjects. In analyzing blood serum with the test, the study reported "near-perfect" classification of patients across all stages of kidney cancer. While urine-based classification was not as accurate, "we believe that performance can ben improved through technical and computational optimization," the authors wrote.

Co-first authors of the report are Pier Vitale Nuzzo, Jacob E. Berchuck, Keegan Korthauer, and Sandor Spisak.

This study was conducted with support from Rebecca and Nathan Milikowsky, the Claudia Adams Barr Program for Innovative Cancer Research, the H.L. Snyder Medical Research Foundation, the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute.