On October 13, 2023 Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported a new study describing a robust artificial intelligence (AI)-based model in partnership with PathAI that accurately predicts luminal muscle invasive urothelial cancer (MIUC), characterized by high peroxisome proliferator-activated receptor gamma (PPARG) expression using H&E-stained slides (Press release, Flare Therapeutics, OCT 13, 2023, View Source [SID1234635957]). This approach supports the clinical development of the Company’s first-in-class clinical candidate, FX-909, for the treatment of patients with advanced Urothelial Carcinoma (UC). These findings were shared at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) being held in Boston, Mass. from October 11-15, 2023.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The digitization of pathology has ushered in a new era of AI and machine learning that can inform patient diagnosis and guide clinical decision-making. We are excited to be at the forefront of applying these innovative biomarker approaches to identify patients with advanced urothelial cancer that may potentially respond to PPARG inhibition," said Michaela Bowden, Chief Development Officer at Flare Therapeutics. "High PPARG expression is a defining feature of luminal MIUC, accounting for approximately 65% of cases in the advanced and metastatic setting. The ability to further stratify patient subsets could offer a powerful tool to inform the path forward for therapy that could include Flare Therapeutics’ lead investigational compound, FX-909."

The poster presentation, titled "AI Analysis of Histological Images Accurately Identifies Luminal Subtype Urothelial Carcinomas Characterized by High PPARG Expression," analyzed H&E-stained slides from 367 unique primary MIUC cases obtained from the TCGA BLCA dataset and 42 MIUC cases from an independent dataset. An end-to-end additive multiple-instance learning model was deployed, resulting in excellent performance typified by AUROC values ³95%, correctly classifying advanced urothelial cancer of luminal subtype, across the test, validation and independent data sets.

"We conducted machine-learning driven analyses of digital images from H&E-stained tissues to identify patients with luminal MIUC," said Michael Montalto, Chief Scientific Officer at PathAI. "We are highly encouraged by the initial results relative to current molecular approaches and look forward to collaborating with the Flare Therapeutics team to evaluate the performance of this novel algorithm in support of the FX-909 program. The model could have tremendous utility in helping to improve MIUC patient outcomes. It was a pleasure to work closely with the Flare Therapeutics team and apply our model to a real-world application."

FX-909 is a first-in-class novel, highly potent and selective small molecule that inhibits PPARG to treat patients with the luminal subtype of advanced UC. The Company recently initiated clinical trials for FX-909.

On October 13, 2023 Anixa Biosciences, Inc. ("Anixa" or the "Company") (NASDAQ: ANIX), a biotechnology company focused on the treatment and prevention of cancer, reported that, in partnership with Moffitt Cancer Center, it has completed treatment of the first patient cohort in the ongoing clinical trial of Anixa’s novel chimeric antigen receptor T-cell (CAR-T) therapy for ovarian cancer (Press release, Anixa Biosciences, OCT 13, 2023, https://www.prnewswire.com/news-releases/anixa-biosciences-completes-treatment-of-first-patient-cohort-in-ovarian-cancer-car-t-clinical-trial-301955685.html [SID1234635956]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

All three patients in the first cohort received the same dose of engineered T-cells, with no dose-limiting toxicities observed. Following the requisite wait time after the last patient was dosed, a comprehensive review of the safety data from this cohort, and confirmation that it is safe to escalate, the trial will begin enrolling patients in the second dose cohort immediately. Patients enrolled in this second cohort will receive three times the cell dose compared to the first cohort.

Dr. Amit Kumar, Chairman and CEO of Anixa Biosciences, stated, "We are pleased with the positive safety data from the first cohort and look forward to advancing to the next higher dose cohort. We hope to continue observing good safety results as we continue to increase dosage, and eventually objective efficacy data."

The study (NCT05316129), which is being conducted at Moffitt Cancer Center, is a dose-escalation Phase 1 trial to evaluate the therapy’s safety; determine the maximum tolerated dose of T-cells targeting the follicle stimulating hormone receptor (FSHR); and preliminarily assess clinical activity. All patients being enrolled in the trial have disease that is progressing and have failed at least two, but often more, therapeutic interventions.

Dr. Robert Wenham, the Principal Investigator of the trial, and the Head of Gynecological Oncology at Moffitt stated, "We are very pleased with the results to date. The first three patients were dosed through a peritoneal catheter and no patient has had a dose-limiting toxicity. Since most lesions in ovarian cancer are within the peritoneum, we hope the delivered CAR-T cells remain localized and active in the vicinity of the tumors. It’s possible that we may see very limited side effects due to this local, as opposed to systemic, delivery. The very selective target also gives us reason to hope that on-target, off-tumor effects will not be prevalent as in other solid tumor studies. Perhaps this delivery approach may enhance efficacy as well. However, we will also test this therapy by intravenous administration, in patients for whom peritoneal administration is not possible."

The CAR-T approach used for Anixa’s therapy is known as chimeric endocrine receptor T-cell (CER-T) since the target of the engineered T-cells is an endocrine receptor. While CAR-T therapy has shown efficacy in some hematological tumors, reproducing the same results with solid tumors, such as ovarian cancer, has proven challenging. One of the reasons for this difficulty is that effective CAR-T therapy needs to attack a specific antigen present only on targeted cells to avoid negatively affecting healthy cells. The cell therapy being evaluated in Anixa’s Phase 1 study differs from traditional CAR-T therapy in that it targets the FSHR, which research indicates is exclusively expressed on ovarian cells in healthy adult females.

On October 13, 2023 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported encouraging preliminary clinical data for RMC-6236, its RASMULTI(ON) Inhibitor, and RMC-6291, its RASG12C(ON) Inhibitor, from the respective Phase 1/1b studies (Press release, Revolution Medicines, OCT 13, 2023, View Source [SID1234635955]). These data were presented during the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) ("Triple Meeting") in Boston, October 11-15, 2023.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are pleased to report encouraging clinical data for both RMC-6236 and RMC-6291, two pioneering RAS(ON) Inhibitors that are providing strong validation of our RAS(ON) Inhibitor platform broadly. The RMC-6236 safety data support that this highly innovative, oral RASMULTI Inhibitor is generally well tolerated across dose levels in patients, exhibits dose-dependent pharmacokinetics reaching exposures predicted preclinically to induce tumor regressions and induces molecular responses (ctDNA) and radiographic regressions suggestive of anti-tumor activity targeting multiple common RAS mutants that cause cancer, including KRASG12D and KRASG12V," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "The RMC-6291 data provide important initial evidence that this mutant-selective, oral RASG12C(ON) Inhibitor can provide mechanistic and clinically meaningful differentiation from KRASG12C(OFF) inhibitors, as indicated by encouraging clinical responses in NSCLC patients previously treated with a KRASG12C(OFF) inhibitor and in KRASG12C(OFF) inhibitor naïve CRC patients at doses that are generally well tolerated."

"These data support our ongoing development of RMC-6236 and RMC-6291, both as monotherapy and in various combinations, including as a RAS(ON) Inhibitor doublet. We will continue evaluating these exciting compounds toward the goal of bringing new and effective therapies to patients living with RAS-addicted cancers, and remain committed to our rich pipeline of differentiated mutant-selective RAS(ON) Inhibitors, as there is significant need for new treatment options."

Phase 1/1b Trial of RMC-6236, RASMULTI(ON) Inhibitor
The Phase 1/1b trial is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-6236 as monotherapy in patients with advanced solid tumors harboring KRASG12X mutations. As of the September 11, 2023 data cut-off, the most common G12 mutations in patients enrolled included G12D (51%); G12V (28%); G12R (11%); G12A (6%); and G12S (4%). Patients with KRASG12C mutations were excluded from the study due to the availability of currently approved KRASG12C(OFF) inhibitors. A total of 131 patients (69 PDAC, 47 NSCLC, 10 CRC, 5 other tumor types) were treated across multiple dose levels administered once daily (QD): 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 200/220 mg, 300 mg, and 400 mg. Patients had received a median of two prior lines of therapy (range 1–7) with standard of care appropriate for tumor type and stage.

As of the data cut-off, RMC-6236 demonstrated an acceptable safety profile that was generally well tolerated across dose levels. The most common treatment-related adverse events (TRAEs) were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity. Of these, the reported Grade 3 TRAEs were rash (5%), stomatitis (2%), and diarrhea (1%). One previously reported Grade 4 TRAE occurred in a PDAC patient at the 80 mg QD dose level who had a large intestine perforation at the site of an invasive tumor that reduced in size while on treatment, which resulted in treatment discontinuation. No safety signals were observed that indicated an elevated risk of hepatotoxicity, which has been reported for some KRASG12C(OFF) inhibitors.

RMC-6236 demonstrated dose-dependent increases in exposure at steady state with minimal accumulation after repeated daily oral dosing, which is compatible with once daily dosing. Clinical exposures achieved at dose levels of 80 mg QD and above were comparable to those that induced tumor regressions in preclinical xenograft models with KRASG12X mutations. Circulating tumor DNA (ctDNA) was assessed in 27 patients with detectable baseline plasma KRASG12X alleles and evaluable for changes in KRAS variant allele frequency (VAF) on-treatment. Molecular responses were observed across two tumor types (NSCLC and PDAC) and 4 different KRAS mutations (KRASG12D, KRASG12V, KRASG12R, and KRASG12A) with reductions in KRAS VAF consistent with anti-tumor activity. Three clinical case reports illustrated tumor regressions induced by RMC-6236 in patients with ovarian cancer (KRASG12V), NSCLC (KRASG12D) or PDAC (KRASG12D).

Phase 1/1b Trial of RMC-6291, RASG12C(ON) Inhibitor
The Phase 1/1b trial is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-6291 as monotherapy in patients with advanced solid tumors harboring KRASG12C mutations. As of the October 5, 2023 data cut-off, a total of 63 patients (23 NSCLC, 33 CRC, 7 with other tumor types) received RMC-6291 at various doses, beginning at 50 mg once daily (QD), escalating to 100 mg QD, 200 mg QD, 100 mg twice daily (BID), 200 mg BID, 300 mg BID and 400 mg BID. Patients across all histologies had received a median of three prior therapies (range 1–7) with standard of care appropriate for tumor type and stage.

As of the data cut-off, RMC-6291 demonstrated preliminary evidence of clinical activity and an acceptable safety profile that was generally well tolerated across dose levels. The activity analysis included 37 patients (17 NSCLC, 20 CRC) who were evaluable for efficacy. Of the 10 NSCLC patients previously treated with a KRASG12C(OFF) inhibitor, 50 percent (n=5; one unconfirmed PR) achieved a partial response (PR) as best response, with a 100 percent disease control rate (DCR). Of the 7 NSCLC patients naïve to KRASG12C(OFF) inhibitors, 43 percent (n=3; two unconfirmed PRs) achieved a PR, with a 100 percent DCR. Among the 20 CRC patients naïve to KRASG12C(OFF) inhibitors, 40 percent (n=8; 3 unconfirmed PRs) achieved a PR as best response, with an 80 percent DCR. The median time to response was 1.3 months (range 1.1–4.1) and 1.4 months (range 1.2–4.1) for NSCLC and CRC patients, respectively. As of the data cut-off, no disease progressions had occurred among patients with an objective response, and 68 percent of all patients remained on treatment.

The most common TRAEs were QTc prolongation and GI-related toxicities that were primarily Grade 1 or 2 in severity. Grade 3 TRAEs were QTc prolongation (11.1%) and diarrhea (1.6%), and only one Grade 3 case was reported with a QTc ≥ 501 msec. All QTc prolongations were asymptomatic with no cardiac sequalae reported. No Grade 4 or 5 AEs or SAEs were reported. Nine patients (14.3%) were dose reduced due to TRAEs, and one patient (1.6%) discontinued treatment due to a Grade 3 QTc prolongation. No safety signals were observed that suggest an increased risk of hepatotoxicity, which has been reported for some KRASG12C(OFF) inhibitors.

Investor Webcast
Revolution Medicines will host an investor webcast on Sunday, October 22, 2023 at 12:30 p.m. Eastern Time to discuss the data presented at both the Triple Meeting and the 2023 European Society for Medical Oncology Congress, in addition to other clinical updates. To participate in the live webcast, participants may register in advance here: View Source A live webcast of the call will also be available on the Investors section of Revolution Medicines’ website at View Source Following the live webcast, a replay will be available on the company’s website for at least 14 days.

On October 13, 2023 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported positive initial data from Modules 1 and 2 of its ongoing Phase 1 MYTHIC clinical trial evaluating lunresertib alone and in combination with camonsertib, an ATR inhibitor (Press release, Repare Therapeutics, OCT 13, 2023, View Source [SID1234635954]). The data are being presented in a plenary session titled, "New Drugs on the Horizon" at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), being held October 11-15, 2023 in Boston, Mass.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Lunresertib (RP-6306) is a first-in-class precision oncology small molecule PKMYT1 inhibitor that targets CCNE1 amplification, FBXW7 and PPP2R1A alterations in solid tumors. Lunresertib is being evaluated alone and in combination with camonsertib (RP-3500 / RG6526), a potent and selective oral inhibitor of ATR developed by Repare and now partnered with Roche for development excluding the lunresertib + camonsertib combination.

"We’re excited by these first clinical proof-of concept results and believe that they further validate the pipeline power of our SNIPRx discovery platform and demonstrate the potential of lunresertib as the only clinical-stage PKMYT1 inhibitor," said Lloyd M. Segal, President and Chief Executive Officer of Repare. "We saw early efficacy signals across multiple tumor types and in each genotype selected, most notably in gynecological tumors where the lunresertib + camonsertib combination provides a potential new treatment option for these patients. Today is an important step forward in Repare’s mission to deliver next-generation precision oncology medicines to patients with genomically-defined tumor alterations predicted by our platform to respond to our candidate drugs."

"The data presented today, although early, are highly promising as lunresertib in combination with camonsertib results in clear clinical activity across several tumor types and genotypes along with a favorable safety and tolerability profile," said Dr. Timothy A. Yap, MBBS, PhD, FRCP, Professor in the Department of Investigational Cancer Therapies (Phase 1 Program) and Vice President, Head of Clinical Development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center and Principal

Investigator on the MYTHIC trial. "These early data suggest treatment with lunresertib in combination with camonsertib could result in efficacy outcomes for patients in the gynecological cancer setting, an area where we’re still seeing unmet patient needs despite current therapies."

Key Initial Findings from the Phase 1 MYTHIC Clinical Trial:

MYTHIC (NCT: NCT04855656), a first-in-human, global, open-label Phase 1 dose-escalation clinical trial to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of lunresertib as a monotherapy (Module 1) or in combination with camonsertib (Module 2) in patients with advanced solid tumors harboring CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations achieved clinical proof of concept. As of September 5, 2023, the cutoff date for the data presented at the AACR (Free AACR Whitepaper)-NCI-EORTC conference, 67 patients were enrolled in Module 1 and 59 patients in Module 2.

•
Protocol-defined overall response (OR) (RECIST or GCIG CA-125 responses) at the combination preliminary recommended phase 2 dose (RP2D) was 33.3% (N=18); CBR at the combination preliminary RP2D (overall response or stable disease of at least 16 weeks without tumor progression) was 50.0%. In all evaluable patients, across all doses (N-55), OR was 23.6% and CBR was 41.8%.

•
In patients with gynecologic tumors at the combination preliminary RP2D (N=10), the RECIST response was 50%, OR 60%, and CBR 70%. Patients in this cohort had a median of 3 and up to 9 prior lines of therapy.

•
RECIST responses in this ongoing combination trial included 8 confirmed and 3 unconfirmed partial responses (PR). Additionally, 3 patients with ovarian tumors had cancer antigen 125 (CA-125) responses.

•
RECIST responses and clinical benefit with combination therapy was seen across all 3 lunresertib-sensitizing alterations: CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations. Molecular response rate (MRR) was significantly higher in combination compared to monotherapy (p=0.003), providing further evidence of enhanced anti-tumor activity: observed MRR in combination therapy was 50% (n=24), compared to 10% (n=30) with lunresertib monotherapy.

•
Encouraging and highly manageable safety and tolerability was observed for the combination therapy (n=59). The most common treatment-related adverse event (TRAE) was anemia, with grade 3 occurring in 42% of patients:

•
Anemia usually improved with a one-week treatment interruption and standard supportive care and did not lead to any therapy discontinuations at preliminary RP2D.

•
There were no Grade 4 or Grade 5 TRAEs reported at preliminary RP2D.

•
Data clearly indicates that anemia management can be individualized and alleviated with simple patient monitoring. This approach is now being tested in the MYTHIC trial.

•
35% of patients did not develop anemia at preliminary RP2D. Generally, those with grade 3 anemia had the lowest hemoglobin values at entry, were intensely pretreated with >4 prior therapies and were of advanced age.

•
Achieved the first clinical proof-of-concept for a synthetic lethal strategy with a PKMYT1 inhibitor combined with an ATR inhibitor in patients with molecularly-selected cancers.

•
Patient enrollment in MYTHIC continues both to optimize the schedule for the combination and to further investigate the promising antitumor signals seen to date in a larger number of patients with selected tumors and genomic alterations.

"The encouraging Phase 1 safety and tolerability profile and early antitumor efficacy data provide proof of concept for lunresertib and clear direction for further development of the chemotherapy-free combination of lunresertib + camonsertib to selectively target the lunresertib-relevant alterations across multiple tumor types, including line of sight on later stage randomized or otherwise definitive studies as the data continue to mature," said Maria Koehler, MD, PhD, Chief Medical Officer of Repare. "This novel, orally delivered combination may provide new therapeutic options in areas of high unmet need, and we look forward to completing the multiple expansions of the Phase 1 MYTHIC study and reporting results in 2024 with later-stage trials expected to initiate shortly thereafter."

Company Virtual Webcast Event:

Repare will host a conference call and webcast today, October 13, 2023, at 5:30 p.m. Eastern Time to discuss the results presented at the AACR (Free AACR Whitepaper)-NCI-EORTC conference, including updated data since the September 5, 2023 data cutoff. Repare’s executive management team will be joined by Dr. Timothy A. Yap, MBBS, PhD, FRCP, Principal Investigator, Professor in the Department of Investigational Cancer Therapies (Phase 1 Program) and Vice President, Head of Clinical Development in the Therapeutics Discovery Division at the University of Texas MD Anderson Cancer Center in Houston, Texas.

To access the call, please dial (877) 870-4263 (U.S. and Canada) or (412) 317-0790 (international) at least 10 minutes prior to the start time and ask to be joined to the Repare Therapeutics call. A live webcast will be available in the Investor section of the Company’s website at View Source . A webcast replay will also be archived for at least 30 days.

On October 13, 2023 Purple Biotech presented its corporate presentation (Presentation, Purple Biotech, OCT 13, 2023, View Source [SID1234635953]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!