On November 10, 2022 SOTIO Biotech, a clinical stage immuno-oncology company owned by PPF Group, reported preclinical data evaluating the mechanism of action and metabolic function of its BOXR T cell platform in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting, taking place in Boston, Massachusetts from November 8-12, 2022 (Press release, SOTIO, NOV 10, 2022, View Source [SID1234626213]). An additional poster was presented on the trial design of AURELIO-04, an ongoing Phase 2 study evaluating the efficacy and safety of SOT101 in combination with pembrolizumab in patients with advanced solid tumors.

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"Preclinical results from the study of our BOXR T cell therapy platform indicate a strong clinical path for our first transgene-expressing CAR-T cell, BOXR1030, as a potential clinical treatment for the 90% of adult cancer patients with solid tumors," said Radek Spisek, M.D., Ph.D., chief executive officer of SOTIO. "The GOT2 infused CAR-T cell therapy improved metabolic fitness, increased cell survival and proliferative capacity of CAR-T cells when exposed to suppressive tumor microenvironments, indicating potentially improved access to solid tumors; a long-standing challenge for CAR-T and other cancer therapies to date. We look forward to initiating first-in-human safety studies of BOXR1030 in the coming months."

Pratirodh Koirala, Ph.D., presenting author from SOTIO Biotech Inc. (U.S.) commented: "CAR-T cell therapy has made significant strides in the treatment of hematological malignancies, yet solid tumors remain resistant to current CAR-T strategies due to suppression by the tumor microenvironment. The preclinical data presented at this year’s SITC (Free SITC Whitepaper) annual meeting demonstrate a promising mechanism of action for SOTIO’s BOXR1030 and underscore the potential that GOT2-expressing CAR-T cells have for enhanced metabolic fitness or more durable early memory phenotypes – benefits which could improve clinical outcomes against solid tumors despite a suppressive tumor microenvironment."

An analysis of the BOXR1030 T cell data show that the BOXR CAR-T cells co-expressing the metabolic gene GOT2 have a higher frequency of less differentiated stem cell memory T cell (TSCM) populations and more CD27+ cells in all memory T cell subsets, suggesting fewer terminally differentiated cells compared to control CAR-T cells lacking the GOT2 transgene. When BOXR1030 T cells were exposed to stressful conditions characteristic of difficult-to-penetrate tumor microenvironments such as low glucose and chronic stimulation, the cells exhibited improved metabolic fitness, increased cell survival and proliferative capacity, multiple characteristics of less differentiated or early memory T cell populations, and retention of effector functions relative to control CAR-T cells.

Dr. Spisek added: "Additionally, progressing our lead clinical asset, SOT101 into the Phase 2 AURELIO-04 study has been a significant clinical milestone for SOTIO. The trial size of 320 patients, all of whom are facing a variety of metastatic cancers that present high unmet needs, will enable us to significantly increase our data pool as SOT101 continues to advance through the clinic."

The design of the Phase 2 AURELIO-04 study, launched by SOTIO in July of 2022, was presented by Aurélien Marabelle, M.D., Ph.D., immuno-oncologist from the Drug Development Department at Gustave Roussy Cancer Center.

The AURELIO-04 study (NCT05256381) is a Phase 2, open-label, single-arm, multicentered study of SOT101 in combination with pembrolizumab to evaluate the efficacy and safety in patients with multiple advanced solid tumor indications. The solid tumor selection was based on previous pembrolizumab studies and/or data from other checkpoint inhibitors (CPI) and includes both CPI-relapsed and/or CPI-naïve tumors. The study will enroll up to a total of approximately 320 patients with a maximum of 50 to 57 per indication in Europe and the United States. SOTIO entered into a clinical trial collaboration and supply agreement with MSD (a tradename of Merck & Co., Inc., Rahway, NJ, USA). MSD supplies KEYTRUDA for the study. In a Phase 1 study, SOT101 in combination with pembrolizumab has reported clinical benefit in 15 out of 19 patients with at least one post-baseline tumor assessment.

Poster presentations from SITC (Free SITC Whitepaper) are available below.

About the BOXR Technology:
SOTIO’s BOXR cell therapy platform is designed to improve the functionality of immune cells such as CAR-T cells by identifying novel "bolt-on" transgenes that can be co-expressed with tumor-targeting receptors to overcome resistance and improve the function of respective immune cells in the solid tumor microenvironment. BOXR-discovered transgenes are selected to address T cell metabolism and overcome multiple mechanisms of immunosuppression, including competition for metabolites, exhaustion due to chronic stimulation, and resistance to immunosuppressive cells.

About SOT101:
SOT101 is a subcutaneously administered IL-15Rβγ superagonist based on IL-15 fused to the sushi+ domain of the IL-15 receptor α chain. SOT101 has demonstrated strong preclinical in vivo efficacy in various tumor models showing increased long-term survival and tumor regression, as well as a favorable toxicology profile. SOT101 has been shown in pre-clinical models to synergize with checkpoint inhibitors and antibody therapies exerting ADCC.

On November 10, 2022 Merck KGaA reported its financial results for third quarter 2022 (Presentation, Merck KGaA, NOV 10, 2022, View Source [SID1234624526]).

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On November 10, 2022 AstraZeneca reported its Year-to-date and Q3 2022 results (Press release, AstraZeneca, NOV 10, 2022, View Source [SID1234624430]).

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On November 10, 2022 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies (tumor infiltrating lymphocyte, TIL, and peripheral-blood lymphocyte, PBL), reported updated clinical data for lifileucel in advanced melanoma during a rapid oral presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, Iovance Biotherapeutics, NOV 10, 2022, View Source [SID1234624237]).

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Amod Sarnaik, M.D., Professor of Cutaneous Oncology and Immunology at H. Lee Moffitt Cancer Center, presenting author and lead C-144-01 trial investigator, stated, "We are excited to present the comprehensive clinical data on behalf of the C-144-01 investigators. The trial demonstrated a robust and clinically meaningful response rate and long-term durability following one-time treatment. Patients in this study were difficult to treat and lacked approved therapies after current standard of care. We hope to offer lifileucel to many more patients after initial progression on immune checkpoint inhibitors."

The oral presentation for the C-144-01 trial included efficacy data from 153 patients with advanced melanoma enrolled in Cohort 2 (n=66) and Cohort 4 (n=87) with a median study follow up of 36.5 months (data cut off July 15, 2022). All patients had progressed on or after immune checkpoint inhibitor (ICI) therapy and targeted BRAF/MEK inhibitor therapy where appropriate. There are no treatments approved by the U.S. Food and Drug Administration (FDA) for the C-144-01 study population. The current available care is chemotherapy (4-10% ORR; median overall survival [mOS] of 7-8 months).1-4

SITC C-144-01 Data Highlights for Pooled Analysis (36.5 Months Median Study Follow Up)

Heavily Pretreated Patient Population with Substantial Disease Burden: Patients had received a median of 3 lines of prior therapy (range 1-9), including anti-PD-1 therapy in 100% of patients (median: 2 lines, range 1-7) and anti-CTLA-4 therapy in 81.7% of patients, with prior combination anti-PD-1 and anti-CTLA-4 therapy received in 53.6% of patients. Baseline disease characteristics were generally similar between Cohorts 2 and 4. However, Cohort 4 patients showed both a higher disease burden (> 3 lesions: 83.9% vs. 65.2%) and a higher proportion of patients with elevated lactate dehydrogenase (LDH; 64.4% vs 40.9%), a well-known negative prognostic factor in melanoma.5

Clinically Meaningful Response Rate and Durability
Clinically Meaningful ORR and Deepening of Responses Over Time: The ORR assessed by an independent review committee (IRC) using RECIST v1.1 was 31.4% (95% CI: 24.1%-39.4%), with 9 complete responses (CRs) and 39 partial responses (PRs). The median time from lifileucel infusion to best response was 1.5 months, and responses deepened over time. Initial PRs converted to CRs in 7 patients, as late as 2+ years post-lifileucel, including 1 conversion to CR in approximately 10 months since the initial data analysis in the abstract.

mDOR (Not Reached) and Durability at 2+ Years: The mDOR was not reached (estimated by Kaplan-Meier, or KM, method). Responses lasted for 24 months or greater in 41.7% of responders (47.8% of responders in Cohort 2; 36.0% of responders in Cohort 4).

Long-Term Benefit from One-Time Lifileucel Therapy: The DOR and overall survival (OS) KM plots show plateaus characteristic of immunotherapy, supporting the potential for long-term benefit from lifileucel therapy. Median (mOS) had not been reached (95% CI: 30.4-NR) in patients who achieved a response at first assessment (6 weeks). mOS in all patients was 13.9 months (95% CI: 10.6-17.8).

Responses Across All Subgroups: Responders to lifileucel included patients with ICI primary-resistant disease, those who received prior anti–CTLA-4 therapy and/or targeted therapies, and responses were observed regardless of PD-L1 status. LDH and target lesion sum of diameters (SOD; tumor mass across locations) were correlated with ORR (P=0.008). Higher odds of response with lower tumor burden suggest that early intervention with lifileucel after ICI may maximize benefit.
Safety: Treatment-emergent adverse events (TEAEs) were consistent with the underlying disease and known AE profiles of nonmyeloablative lymphodepletion and interleukin-2 (IL-2). Incidence of TEAEs decreased rapidly within the first 2 weeks after lifileucel infusion.

94.7% Manufacturing Success Rate: All patients in both cohorts received the same lifileucel treatment using Iovance’s proprietary 22-day manufacturing process (Gen 2). Lifileucel was manufactured within specification in 94.7% of patients across Cohorts 2 and 4.
Friedrich Graf Finckenstein, M.D., Chief Medical Officer of Iovance, stated, "Our C-144-01 trial is the largest clinical trial of a cell therapy in advanced melanoma following anti–PD-1 therapy and the basis for our rolling BLA submission for lifileucel. We observed responses across the spectrum of patients with advanced melanoma, including early responses and deepening responses over time, following anti-PD-1 and anti-CTLA-4 therapy, and regardless of mutation and PD-L1 status. Given the correlation of lower tumor burden and response, we believe there is a strong rationale for treatment with lifileucel as soon as possible after initial progression on anti–PD-1 therapy. The potential for long-term benefit from one-time treatment with lifileucel is promising, as the overall survival data show the desired plateau of maintained benefit with immunotherapy, and include patients who are alive five years after treatment."

The C-144-01 results are available in the oral presentation slide deck on the Iovance corporate website. Data from the pivotal Cohort 4, supportive data from Cohort 2 and the pooled analysis of Cohorts 2 and 4 are part of a rolling Biologics License Application (BLA) submission to the FDA for lifileucel in advanced melanoma, which Iovance initiated in August 2022.

Investor Webcast on Thursday, November 10, 4:30 p.m. ET
Iovance will host a webcast on Thursday, November 10 at 4:30 p.m. ET to discuss clinical data updates for lifileucel in advanced melanoma. Iovance senior leadership will be joined by the following key opinion leaders and principal investigators in Iovance clinical studies: Amod Sarnaik; Allison Betof Warner, M.D., Ph.D., Assistant Attending Physician and Melanoma Medical Oncologist, Memorial Sloan Kettering Cancer Center; Miguel Perales, M.D., Chief, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center; and Martin McCarter, M.D., Surgical Director for the Esophageal and Gastric Multidisciplinary Clinic, Vice Chair for Strategy and Program Development Department of Surgery, UCHealth Cancer Care – Anschutz Medical Campus – University of Colorado Cancer Center. The live and archived webcast can be accessed in the Investors section of the company’s website here: View Source

On November 10, 2022 Rain Therapeutics Inc. (NasdaqGS: RAIN), (Rain), a late-stage biotechnology company developing precision oncology therapeutics with a lead product candidate, milademetan, an oral, small molecule inhibitor of the MDM2-p53 complex that reactivates p53, reported financial results for the third quarter ended September 30, 2022, along with an update on the Company’s key developments, business operations and upcoming milestones (Press release, Rain Therapeutics, NOV 10, 2022, View Source [SID1234624021]).

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"Rain continues to execute on our milademetan franchise with encouraging early interim data from our Phase 2 MANTRA-2 trial and anticipated near-term topline data from our Phase 3 registrational MANTRA trial next quarter," said Avanish Vellanki, co-founder and chief executive officer of Rain. "The preliminary observations of monotherapy activity of milademetan in the MANTRA-2 trial demonstrates encouraging data in a novel biomarker-based tumor agnostic strategy and supporting potential in additional MDM2-dependent cancers."

Dr. Robert Doebele, MD, PhD, president and chief scientific officer of Rain continued, "Preliminary data from the MANTRA-2 trial exhibited activity with two unconfirmed partial responses (PRs) at their first scan and promising tumor regression activity in two additional patients following milademetan monotherapy. We are very encouraged to see proof of concept activity using a genetic selection strategy across a diverse set of solid tumor types in heavily pre-treated patients, and those that possess multiple genetic co-alterations including strong oncogenic driver mutations. We believe the early activity suggests reactivation of p53 in MDM2-dependent cancers and may represent a sound therapeutic strategy with single-agent milademetan, and possibly through combination regimens as well."

Dr. Richard Bryce, MBChB, chief medical officer of Rain continued, "We have also observed this promising activity from the MANTRA-2 trial in patients with MDM2 copy number above 8. Hence, we plan to revise the protocol to include patients tested locally for MDM2 copy number of 8 and greater and anticipate this will further enhance the pace of enrollment to expedite completion of the 65-patient trial. We plan to initiate the MANTRA-4 trial next quarter and remain very excited about this second tumor agnostic basket strategy."

Key Corporate Updates and Upcoming Milestones

$50.0 Million Registered Offering of Common Stock
Completed a $50.0 million registered offering of common stock and non-voting common stock on November 8, 2022
End of third quarter cash balance of $90.7 million excludes the $50.0 million registered offering
Phase 3 MANTRA Trial of Milademetan in Dedifferentiated Liposarcoma
Topline data now anticipated in the first quarter of 2023
Phase 2 Preliminary Interim Data for the MANTRA-2 Basket Trial of Milademetan for MDM2-Amplified Advanced Solid Tumors
As of October 26, 2022, ten patients were efficacy-evaluable with CN ≥8 by central testing
Two unconfirmed PRs were observed with tumor regression of 34% and 30% (pancreatic and lung cancer, respectively)
The patient with pancreatic cancer is pending response confirmation and ongoing treatment
The patient with lung cancer is deceased due to COVID-19
Two patients exhibited promising activity with tumor regression of 29% and 27% (biliary tract and breast cancer, respectively) and the patients are continuing with the investigational therapy
Observed rapid anti-tumor effect of milademetan in heavily pretreated, refractory patients, with a median of four prior therapies
Safety profile to date is preliminarily consistent with prior Phase 1 milademetan trial
Phase 2 MANTRA-3 Trial in Merkel Cell Carcinoma Deprioritized
MANTRA-3 is deprioritized to rationalize use of financial and personnel resources
Phase 1/2 MANTRA-4 Basket Trial in Advanced Solid Tumors Exhibiting Loss of the CDKN2A Gene
Commencement of MANTRA-4, the trial to evaluate the combination of milademetan with Roche’s FDA-approved IO therapy, atezolizumab, planned for first quarter of 2023
Recent addition to our Scientific Advisory Board, Nicholas A. Saccomano, Ph.D. in September 2022
Dr. Saccomano is the former Chief Scientific Officer of Array Biopharma, and a seasoned leader and mentor with over 30 years of experience in pharmaceutical and biotechnology research and development
Our updated corporate presentation includes details of the preliminary interim data for MANTRA-2 and is available at the "Corporate Presentation" section of the Rain website.

Third Quarter Financial Results
For the three and nine months ended September 30, 2022, Rain reported a net loss of $18.0 million and $53.0 million, respectively, as compared to a net loss of $18.4 million and $33.4 million for the same periods in 2021, respectively.

Research and development (R&D) expenses were $14.5 million and $42.3 million for the three and nine months ended September 30, 2022, respectively, as compared to $15.3 million and $26.1 million for the same periods in 2021, respectively. The decrease for the three months ended September 30, 2022 as compared to the prior period was primarily due to the milestone fees to Daiichi Sankyo of $5.5 million incurred during the prior period, partially offset by various R&D costs for milademetan, as well as higher payroll-related costs for Rain’s R&D personnel. The increase for the nine-months ended September 30, 2022 as compared to the prior period was primarily driven by the ongoing MANTRA Phase 3 trial in liposarcoma and Phase 2 tumor-agnostic basket trial (MANTRA-2), as well as personnel costs and various other R&D costs for milademetan. Non-cash stock-based compensation expenses included in R&D expenses were approximately $0.7 million and $2.8 million in the three and nine months ended September 30, 2022, respectively, as compared to $0.7 million and $1.4 million in the same periods in 2021, respectively.

General and administrative (G&A) expenses were $3.9 million and $11.3 million for the three and nine months ended September 30, 2022, respectively, as compared to $3.2 million and $7.3 million for the same periods in 2021, respectively. The increases were primarily due to higher payroll-related costs for Rain’s G&A personnel, outside consulting, legal costs and various third-party G&A costs. Non-cash stock-based compensation expense included in G&A expenses were approximately $0.2 million and $0.8 million for the three and nine months ended September 30, 2022, as compared to $0.2 million and $0.4 million for each of the same periods in 2021.

Total non-cash stock-based compensation expense were approximately $0.9 million and $3.6 million for the three and nine months ended September 30, 2022, respectively, as compared to $0.9 million and $1.8 million for the same periods in 2021, respectively.

As of September 30, 2022, Rain had $90.7 million in cash, cash equivalents and short-term investments as compared to $140.2 million at December 31, 2021. On November 8, 2022, Rain completed a $50.0 million registered offering of common stock and non-voting common stock, and together with the cash balance as of September 30, 2022 provides cash runway into 2025.

As of September 30, 2022, Rain had approximately 26.6 million shares of common stock outstanding.

Third Quarter 2022 Results Conference Call and Webcast Details
The management of Rain Therapeutics will host a conference call and webcast for the investment community today, November 10, 2022 at 2:00 pm PT (5:00 pm ET). A live webcast may be accessed here. The conference call can be accessed by dialing 1 (877) 704-4453 (U.S. Toll Free) / 1 (201) 389-0920 (International). The passcode for the conference call is 13733093.

Replay of the call will be available by visiting the "Events" section of the Rain website after the conclusion of the presentation and will be archived on the Rain website for 30 days.

About MANTRA-2

The MANTRA-2 trial is designed to evaluate the safety and efficacy of milademetan monotherapy in patients with advanced or metastatic solid tumors refractory or intolerant to standard-of-care therapy and that exhibit wild-type p53 and a prespecified minimum MDM2 gene copy number. Approximately 65 patients are anticipated to be enrolled to receive milademetan. As of the latest data cutoff on October 26, 2022, 17 patients have been enrolled. The primary endpoint of the trial is objective response rate as measured by RECIST criteria. Secondary endpoints include duration of response, disease control rate progression-free survival by investigator assessment, overall survival and growth modulation index.

About Milademetan

Milademetan (also known as RAIN-32) is an oral small molecule inhibitor of the MDM2-p53 complex that reactivates p53.Milademetan has demonstrated antitumor activity in an MDM2-amplified subtype of liposarcoma (LPS) and other solid tumors in a Phase 1 clinical trial, supported by a rationally designed dosing schedule to mitigate safety concerns and widen the potential therapeutic window of MDM2 inhibition. Rain has completed enrollment in a Phase 3 trial of milademetan (MANTRA) in patients with LPS, and is evaluating milademetan in a Phase 2 tumor-agnostic basket trial in certain solid tumors (MANTRA-2). Rain anticipates commencing a Phase 1/2 clinical trial to evaluate the safety, tolerability and efficacy of milademetan in combination with Roche’s atezolizumab in patients with loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and wildtype p53 advanced solid tumors (MANTRA-4), in the first quarter of 2023. Milademetan has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of LPS.