On June 6, 2022 Molecular Templates, Inc., (Nasdaq: MTEM, "Molecular Templates" or "MTEM") a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs), reported highlights from the two poster presentations on its clinical programs that were presented on June 5th at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, taking place June 3 through June 7, 2022 at the McCormick Place Convention Center in Chicago, IL (Press release, Molecular Templates, JUN 6, 2022, View Source [SID1234615641]). Copies of the posters presented at ASCO (Free ASCO Whitepaper) can be found in the "Investors" section of Molecular Templates’ corporate website under Presentations.

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"ETBs offer novel biology with the potential to drive unique clinical outcomes, even against well-explored targets," said Eric Poma, Ph.D., CEO and CSO of Molecular Templates. "We are seeing differentiated pharmacodynamic effects and signs of clinical benefit in patients in our on-going Phase I study with MT-6402, our PD-L1 targeting agent, from both that agent’s direct cell-kill effects and its antigen seeding ability. For MT-5111, our HER2-targeting agent, we have achieved exposures in dose-escalation with which have generated pharmacodynamic effects that may be associated with clinical benefit."

Poster Title: First-in-human, dose escalation and expansion study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing relapsed/refractory advanced solid tumors: Interim Data

Authors: Eugene Ahn, MD; Brian Van Tine, MD; John D. Powderly, MD; Herbert L. Duvivier, MD, JD; Drew Rasco, MD; Agnes Rethy, MD; Chris Moore, PhD; Amy Yuet, PhD; Rachael M. Orlandella, PhD; Swati Khanna, PhD; Joseph D. Dekker, PhD; Angela Georgy, PharmD; David R. Spigel, MD

Abstract #: 2521

Poster highlights:

Data were presented on 12 patients with PD-L1+ relapsed/refractory disease across two dose cohorts: 16 mcg/kg (n=6) and 24 mcg/kg (n=6). Treatment is on-going in the 32 mcg/kg cohort with no dose-limiting toxicities (DLTs) observed to date in the third cohort.
Pharmacodynamic (PD) effects including PD-L1+ dendritic cell and monocyte cell depletion and T cell activation have been observed in the majority of patients. The extent and timing of these PD effects appear dose-related with patients in the 24 mcg/kg cohort generally showing a more rapid and profound PD effect. Patients in both cohorts demonstrated increases in IL-2.
One patient in the first cohort with non-small cell lung cancer (NSCLC) (osseous non-measurable disease only) that had progressed after prior checkpoint therapy (PD-1 and CTLA-4) showed qualitative reduction in tumor burden.
One DLT was observed in a single patient (24 mcg/kg) who experienced dermatitis that resolved rapidly with systemic steroids. The patient was rechallenged without incident at 24 mcg/kg. No other DLTs have been reported.
Based on these findings, monotherapy will continue to be investigated and a combination approach with a PD-1 inhibitor is also being considered for select populations of patients.
Poster Title: A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: interim results

Authors: Brian A. Van Tine, MD, PhD; Joleen M. Hubbard, MD; Monica M. Mita, MD; Minal A. Barve, MD; Erika P. Hamilton, MD; Frances Valdes, MD; Daniel Ahn, DO; Joshua Pelham; Admasu Mamuye, MD; Amy Yuet, PhD; Diana Yurewicz, MPH; Yanning Liu, PhD, Taunya Smith, MPH; Andrés Machado Sandri, MD; William J. Edenfield, MD; Aki Morikawa, MD, PhD; Meena Okera, MD; Zev A. Wainberg, MD

Abstract #: 2583

Poster highlights

Data were presented on 35 patients with HER2+ relapsed/refractory disease across eight dose cohorts ranging from 0.5 mcg/kg to 13 mcg/kg (N=31) and the breast cancer expansion cohort (N=4): Treatment is on-going with the 17 mcg/kg cohort having been closed and dosing has begun in the 23 mcg/kg cohort.
No Grade 4 or 5 treatment emergent adverse events or DLTs have been identified in 35 patients, including 2 patients who were treated for 6 months or longer.
Serum concentration of MT-5111 showed predictable and dose-proportional increasing exposure in the last three evaluable dose cohorts.
Higher MT-5111 doses (6.75 mcg/kg and above) appear to saturate circulating soluble HER2 (sHER2) receptors with patients’ HER2 levels stabilizing or decreasing at higher doses.

On June 6, 2022 Novartis reported Tafinlar (dabrafenib) + Mekinist (trametinib) significantly improved efficacy in patients ages 1 to 17 years old with BRAF V600 pediatric low-grade glioma (pLGG) requiring first systemic treatment compared to chemotherapy, the current standard-of-care for these patients1 (Press release, Novartis, JUN 6, 2022, View Source [SID1234615640]). In this study, patients randomized to receive Tafinlar + Mekinist experienced a statistically significant overall response rate (ORR) of 47% (CI: 35-59%) compared to 11% (CI: 3-25%, p<0.001) for those randomized to receive chemotherapy. A new liquid formulation of Tafinlar + Mekinist that can be easier to administer than chemotherapy was used in this trial. The data will be highlighted today as part of an official press briefing and oral presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #LBA2002).

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"These results show dabrafenib and trametinib demonstrate an improvement over chemotherapy for children and adolescents with BRAF V600 low-grade gliomas," said Eric Bouffet, MD, FRCPC, Senior Associate Scientist Emeritus at The Hospital for Sick Children (SickKids) in Toronto, Canada. "This work highlights the importance of testing for mutations like BRAF in patients with low-grade gliomas."

LGG is the most common pediatric brain cancer and BRAF V600 mutations are present in 15-20% of pLGGs2,5. Currently, standard chemotherapy is associated with poor outcomes and a high burden of care6.

Additional results from the Phase II/III trial showed at a median follow-up of 18.9 months, median progression-free survival (PFS) was 20.1 months with Tafinlar + Mekinist (CI: 12.8 months-not estimable) compared to 7.4 months with chemotherapy (CI: 3.6-11.8 months, hazard ratio=0.31 [CI: 0.17-0.55] [p<0.001])1. Additionally, tumors shrank or remained stable in 86% of patients in the Tafinlar + Mekinist arm (n=73; CI: 76-93%) compared to 46% of patients in the chemotherapy arm (n=37; CI: 30-63%). After one year of follow-up, nearly all patients on Tafinlar + Mekinist (89%) had a reduction in tumor size compared with baseline versus 70% of patients in the chemotherapy arm. Results from a quality-of-life analysis favored Tafinlar + Mekinist compared to chemotherapy at all time points1.

"These young patients and their families experience a heavy burden of care as BRAF V600 low-grade glioma poses a risk of neurological impairment and current standard-of-care treatment is intravenous and associated with frequent trips to the cancer clinic or hospital," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development at Novartis. "Tafinlar + Mekinist has shown unprecedented efficacy, and we will work with health authorities to bring these children the possibility of a more effective and easier to administer liquid oral treatment option as quickly as possible."

The safety profile of Tafinlar + Mekinist was generally consistent with established safety observed in previous studies. Patients in the Tafinlar + Mekinist arm had fewer grade 3 or higher adverse events (AEs; 47% vs 94%) and fewer discontinuations due to AEs (4% vs 18%) than patients in the chemotherapy arm evaluated for safety (n=33)1. The most frequent AEs in the Tafinlar + Mekinist arm were pyrexia, headache and vomiting1.

In a separate single-arm cohort of this study evaluating pediatric patients with relapsed or refractory BRAF V600 high-grade gliomas (HGG), treatment with Tafinlar + Mekinist showed an independently assessed ORR of 56.1% [CI: 39.7%-71.5%] and generally consistent safety results4. These data were presented in a poster discussion at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting (Abstract #2009).

Tafinlar + Mekinist was granted Breakthrough Therapy designation by the US Food and Drug Administration for the treatment of pediatric patients one year of age and older with LGG with a BRAF V600E mutation who require systemic therapy.

About the TADPOLE trial
This global Phase II/III, multicenter, open-label trial is evaluating patients aged 1 to 17 with BRAF V600 LGG (n=110) or relapsed or refractory HGG (n=41)1. Tafinlar + Mekinist is administered orally either as new liquid formulations, or as capsules and tablets, respectively. The primary endpoint in both cohorts is overall response rate. Secondary outcome measures include duration of response, progression-free survival, overall survival and other endpoints1.

About pediatric gliomas
Gliomas are the most common pediatric central nervous system tumor type, representing about half of all pediatric brain cancers5,7,8. Gliomas are classified as either low-grade (grades 1 and 2) or high-grade (grades 3 and 4)7.

Pediatric low-grade gliomas positive for the BRAF V600E mutation have been associated with worse survival outcomes (OS/PFS) and are found in approximately 15-20% of pLGG2,3. BRAF mutations are found in approximately 3% to 7% of people with HGG (all ages combined)9,10.

BRAF mutations have been identified as drivers of cancer growth across a wide range of solid tumors and often have limited treatment options11,12.

About Tafinlar + Mekinist
The combination of Tafinlar + Mekinist, the worldwide targeted therapy leader in BRAF/MEK-inhibition research and patients reached, may help to slow tumor growth by blocking signals associated with the BRAF and MEK kinases, which are implicated in the growth of various types of cancer11-15. Tafinlar + Mekinist has been studied in more than 6,000 BRAF-positive patients in more than 20 ongoing and completed trials and has been prescribed to more than 200,000 patients worldwide15.

Tafinlar + Mekinist is currently not approved for pediatric patients with LGG or HGG. These results will form the basis of regulatory discussions with global health authorities.

On June 6, 2022 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for people living with cancer, reported an update from an interim analysis of its international Phase 2 RAMP 201 trial evaluating VS-6766 ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC), regardless of KRAS status (Press release, Verastem, JUN 6, 2022, View Source [SID1234615639]).

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Verastem recently completed a planned interim analysis of its RAMP 201 trial with the goal of selecting a go forward treatment regimen of either VS-6766 monotherapy or VS-6766 in combination with defactinib. The analysis indicated encouraging efficacy results with confirmed responses by independent review in patients treated with VS-6766 monotherapy and patients treated with VS-6766 in combination with defactinib. The findings also include confirmed responses by independent review in both KRAS mutant and KRAS wild-type LGSOC. To date, there have been no additional safety signals with a continued favorable safety profile in both the monotherapy and combination treatment arms with approximately 6% of patients discontinuing due to adverse events.

With a substantial majority (approximately 80%) of patients remaining on study treatment with a median duration of follow-up of four months, the Company has concluded that the data from the interim analysis are not mature enough to make a final decision on the go forward treatment regimen at this time and the trial will continue with all four cohorts (VS-6766 ± defactinib in KRAS mutant and KRAS wild type patient populations).

"We are encouraged by the positive anti-tumor activity that we have seen to date in the RAMP 201 trial in patients with both KRAS mutant and KRAS wild-type tumors. We look forward to evaluating a more mature data set and expect to provide an update on progress once the go forward treatment regimen has been determined," said Brian Stuglik, Chief Executive Officer, Verastem Oncology. "This interim analysis adds to our optimism about the potential for VS-6766 with or without defactinib and our commitment to advancing the first new treatment specifically developed and approved for women with low-grade serous ovarian cancer where a high medical need remains."

The Company plans to complete enrollment of all four cohorts of the trial in the second half of this year. Each cohort is expected to have approximately 36 patients for a total of 144 patients.

Both VS-6766 and defactinib are in late-stage development and the combination has received Breakthrough Therapy Designation by the U.S. Food and Drug Administration for the treatment of all patients with recurrent low-grade serous ovarian cancer regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

About the VS-6766/Defactinib Combination

VS-6766 is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS pathway inhibition. In contrast to currently available MEK inhibitors, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and FAK inhibitor, defactinib provides RAF/MEK vertical blockade and FAK parallel inhibition to overcome key resistance mechanisms. Both VS-6766 and defactinib are in late-stage development.

Verastem Oncology is conducting Phase 2 registration-directed trials of VS-6766 alone and with defactinib in patients with recurrent LGSOC and in patients with recurrent KRAS G12V-mutant NSCLC as part of its RAMP (Raf And Mek Program) clinical trials, RAMP 201 and RAMP 202, respectively (www.ramp201study.com and www.ramp202study.com). Verastem Oncology has also established clinical collaborations with Amgen, Inc. and Mirati Therapeutics, Inc. to evaluate LUMAKRAS (sotorasib) and adagrasib in combination with VS-6766 in KRAS G12C-mutant NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively.

About Low-Grade Serous Ovarian Cancer

Low-grade serous ovarian cancer is a highly recurrent, chemotherapy-resistant cancer, associated with slow tumor growth and high mortality rate.1 Approximately 6,000 women in the U.S. and 80,000 worldwide are living with this disease. Mutations in the KRAS gene are present in 35-57% cases of LGSOC.2 LGSOC is most often diagnosed in women between the ages of 45-55 years and has a median survival of approximately ten years.2 The majority of patients experience severe pain and complications as the disease progresses. Chemotherapy is the standard of care for this disease, with limited treatment options currently available.2

On June 6, 2022 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported that it presented updated preliminary Phase I data on TG4050, its individualized neoantigen cancer vaccine, in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Transgene JUN 6, 2022, View Source [SID1234615638]). TG4050 is based on Transgene’s myvac platform and powered by NEC’s cutting-edge AI capabilities.

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These additional positive initial data, including molecular (ctDNA) response, have been generated from the first patients with ovarian cancer and HPV-negative head and neck cancer enrolled in the two ongoing Phase I trials assessing TG4050. They were presented in-person in Chicago, IL, June 5, 2022.

"These new results, though early, are very encouraging" said Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene. "So far we accumulated promising preliminary data with TG4050: good tolerability, consistent immunogenicity and encouraging molecular response. We are particularly impressed by the effective priming of the immune system and the early signs of clinical activity. These results suggest that our individualized vaccine, TG4050, has the potential to extend the remission period, thus providing a new hope for cancer patients. In addition, the information we gather from the two ongoing Phase I studies will be pivotal in designing the Phase II trial of TG4050 which could start as early as 2023."

Prof. Jean-Pierre Delord, MD, PhD, General Manager of IUCT Oncopole of Toulouse and first author of the poster, added: "Neoantigen vaccination such as TG4050 is a relevant strategy for the treatment of patients with high risk of cancer relapse for whom the medical need is particularly high. In this setting, the vaccine is expected to deliver clinical benefit by controlling the residual disease. To date, this non-invasive treatment is well tolerated by the patients and although preliminary, the data presented at ASCO (Free ASCO Whitepaper) clearly suggest that TG4050 could become a new treatment option for cancer patients. I am looking forward to seeing this potential game-changing therapy moving forward."

For the first time, ctDNA data were generated following treatment with TG4050

Liquid biopsies were performed to measure the circulating tumor DNA (ctDNA) levels. ctDNA is an emerging modality that is used to detect subclinical disease or asymptomatic relapse in an increasing number of indications. Use of such highly sensitive and specific marker seeks to identify patients whose disease is very likely to relapse in the near future, before their disease becomes detectable with current standard methods such as imaging. Moreover, it allows a non-invasive monitoring of treatment effectiveness. For instance, in at least one ovarian cancer patient in the study, a decline in ctDNA was concomitant with CA-125 normalization and disease control. Analyses are ongoing in more recently included patients.

Clinical follow-up data continue to demonstrate the potential of TG4050 in ovarian and head and neck cancer patients

In the head and neck cancer trial, patients were randomized to immediately receive vaccination with TG4050 (early treatment arm, arm A) or at relapse (delayed vaccination arm, arm B). All evaluable patients randomized to arm A (n=8) are still in complete response as of mid-May 2022. In arm B (n=8), two patients have experienced relapse.

In the ovarian cancer trial (n=5), a fifth patient initiated her treatment with TG4050 recently. One patient treated after an elevation of CA-125 experienced a normalization of CA-125 without clinical progression for 9 months until death from an unrelated chronic illness. Another patient was treated upon onset of radiological evidence of relapse and remained stable for 11.4 months.

To date, the vaccine has been well tolerated and no related Serious Adverse Events have been reported across the two studies.

In both clinical studies, enrollment and patient dosing are progressing in line with our expectations. Overall, Transgene plans to treat 13 patients in the ovarian cancer trial and 30 patients in the head and neck cancer trial.

Immune cell response data demonstrated an effective priming of the immune system which is associated with disease regression

Transgene presented a comprehensive set of immunological data at ASCO (Free ASCO Whitepaper). Circulating immune cells quantification (in particular monocytes, DC, NK cells, subcells of CD8, CD4, Treg) and expression of immune checkpoints (ICOS and PD1) suggest that the vaccine is able to effectively induce innate and adaptive immune responses in patients.

In an ovarian cancer patient, clinical resolution and biological responses (CA-125 and ctDNA responses) were concomitant to an immune response against multiple epitopes and to the onset of markers of an effective immune response (switch in circulating CD4 and CD8 cells toward an effector phenotype, increase in CD16neg NK cells; peak in circulating cytokines).

All evaluable patients developed a robust T-cell response against multiple targeted neoantigens (median of 10 positive responses per patient). T-cell responses were observed for class I and class II epitopes, they consisted of de novo responses and amplifications of preexisting responses.

Poster title: Phase 1 studies of personalized neoantigen vaccine TG4050 in ovarian carcinoma (OC) and head and neck carcinoma (HNSCC)

Abstract number: 2637
Session title: Developmental Therapeutics—Immunotherapy
Authors: J.P. Delord, M. Block, C. Ottensmeier, G. Colon-Otero, C. Le Tourneau, A. Lalanne, O. Lantz, KL. Knutson, G. Lacoste, A. Tavernaro, M. Brandely, N. Silvestre, B. Grellier, Y. Yamashita, O. Kousuke, N. Yamagata, Y. Tanaka, B. Malone, E. Quemeneur, K. Bendjama

About the clinical trials

TG4050 is being evaluated in two Phase I clinical trials for patients with ovarian cancer (NCT03839524) and HPV-negative head and neck cancers (NCT04183166).

In a first Phase I trial, TG4050 is being administered to patients with HPV-negative head and neck cancer. A personalized treatment is created for each patient after they complete surgery and while they receive an adjuvant therapy. Half of the participants receive their vaccine immediately after they complete their adjuvant treatment. The other half is given TG4050 as an additional treatment at the time of recurrence of the disease as an additional treatment to SoC. This randomized study is evaluating the treatment benefits of TG4050 in patients who have a high risk of relapse. Up to 30 patients will receive TG4050 in France, in the UK and in the USA. The principal investigator of the trial is Prof. Christian Ottensmeier, MD, PhD, Consultant Medical Oncologist at the Clatterbridge Cancer Centre and Professor of Immuno-Oncology at the University of Liverpool. In France, the clinical trial is being conducted at Institut Curie, Paris by Prof. Christophe Le Tourneau, MD, PhD, Head of the Department of Drug Development and Innovation (D3i), and at the IUCT-Oncopole, Toulouse by Prof. Jean-Pierre Delord, MD, PhD. In the USA, the trial is being led by Yujie Zhao, MD, PhD, at the Mayo Clinic. Endpoints of the trial include safety, feasibility and biological activity of the therapeutic vaccine.

In parallel, a Phase I clinical trial of TG4050 is enrolling patients with ovarian cancer. This second trial is including patients at the time of asymptomatic relapse after surgery and first-line chemotherapy. Matthew Block, MD, PhD, Consultant Medical Oncology, Consultant Immunology and Associate Professor of Oncology at the Mayo Clinic (USA) is the principal investigator of the trial; in France, the trial is being conducted by Prof. Le Tourneau, MD, PhD, at Institut Curie and by Alexandra Martinez, MD, Associate Head of Surgical Department, at IUCT-Oncopole. Endpoints of the trial include safety, feasibility and biological activity of the therapeutic vaccine.

The first preliminary clinical data generated from the first patients treated with TG4050 were very encouraging.

About myvac

myvac is a viral vector (MVA – Modified Vaccinia Ankara) based, individualized immunotherapy platform that has been developed by Transgene to target solid tumors. myvac-derived products are designed to stimulate the patient’s immune system, recognize and destroy tumors using the patient’s own cancer specific genetic mutations. Transgene has set up an innovative network that combines bioengineering, digital transformation, established vectorization know-how and unique manufacturing capabilities. Transgene has been awarded "Investment for the Future" funding from Bpifrance for the development of its platform myvac. TG4050 is the first myvac-derived product being evaluated in clinical trials.

Click here to watch a short video on myvac.

About TG4050

TG4050 is an individualized immunotherapy being developed for solid tumors that is based on Transgene’s myvac technology and powered by NEC’s longstanding artificial intelligence (AI) expertise. This virus-based therapeutic vaccine encodes neoantigens (patient-specific mutations) identified and selected by NEC’s Neoantigen Prediction System. The prediction system is based on more than two decades of expertise in AI and has been trained on proprietary data allowing it to accurately prioritize and select the most immunogenic sequences.

TG4050 is designed to stimulate the immune system of patients in order to induce a T-cell response that is able to recognize and destroy tumor cells based on their own neoantigens. This individualized immunotherapy is developed and produced for each patient.

On June 6, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results of a prospective analysis from the Phase 1b cohort of the KRYSTAL-1 study evaluating intracranial (IC) responses of adagrasib in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases (Press release, Mirati, JUN 6, 2022, View Source [SID1234615636]). This is the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC with active and untreated CNS metastases. Findings show that approximately one third of the patients had an IC response in patients with CNS metastases, consistent with what was observed systemically in this cohort.

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The data will be presented today as a late-breaking oral presentation in the session titled, "Clinical Science Symposium/Including the Excluded: Advancing Care for All Patients With Lung Cancer" at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from 5:30 to 5:42 PM ET/4:30 to 4:42 PM CT (Abstract #LBA9009).

"We are proud to share the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC," said Charles Baum, M.D., Ph.D., president, founder and head of research and development, Mirati Therapeutics, Inc. "Central nervous system metastases disproportionately affect patients with NSCLC and should be carefully considered as part of the treatment approach. Adagrasib showed CNS penetration and intracranial responses in patients with active and untreated CNS metastases, demonstrating potential as a treatment option for this underserved patient population."

Results of Prospective Analysis

With a median follow up of 6.6 months (data cutoff date December 2021), 25 patients with active, untreated CNS metastases were enrolled in the study and treated with adagrasib 600 mg BID.

Of the radiographically evaluable patients (n=19), results showed an IC objective response rate of 32% (6/19) by modified response assessment in neuro-oncology-brain metastases (modified RANO-BM) by blinded independent central review.

In this analysis, three patients achieved a complete response and three patients achieved a partial response. The IC disease control rate was 84% (16/19, including 10 patients with stable disease). The median IC duration of response was not reached (95% confidence interval: 4.1 – not evaluable). Concordance of disease control between systemic and IC responses was 88% (14/16). For all patients enrolled, median overall survival was not reached.

Cerebrospinal fluid (CSF) samples were obtained from two patients for whom regression of CNS metastases was observed; adagrasib CSF/free plasma concentration ratios (Kp,uu: 0.47) were consistent with other agents with known CNS penetration and activity.

The safety profile of adagrasib in this study was consistent with the overall population with no new safety signals observed. Grade 1 and 2 treatment related adverse events (TRAEs) occurred in 60% of patients. Grade 3 TRAEs occurred in 36% of patients, and there were no Grade 4/5 TRAEs.
"Central nervous system metastases occur in 27% to 42% of patients with KRASG12C-mutated NSCLC at diagnosis. These patients have a median overall survival of approximately five months, posing a serious clinical challenge," said Joshua K. Sabari, M.D., assistant professor of medicine, medical oncology at Perlmutter Cancer Center, NYU Langone Health. "With a median follow up of 6.6 months, these early and positive data show adagrasib demonstrated a meaningful overall intracranial response rate with early indications for overall survival. Adagrasib warrants further investigation on its potential to improve clinical outcomes for NSCLC patients harboring a KRASG12C-mutation who have active and untreated CNS metastases, including opportunities through Mirati’s Expanded Access Program."

Mirati also presented results from the registration-enabling Phase 2 cohort of the KRYSTAL-1 study evaluating adagrasib in patients with pre-treated NSCLC harboring a KRASG12C mutation during the Lung Cancer–Non-Small Cell Metastatic session at ASCO (Free ASCO Whitepaper) on June 3, 2022.

Virtual Investor Event

Mirati Therapeutics will host an Investor Event on Monday, June 6, 2022, at 8:00 PM ET/ 7:00 PM CT.

Company executives will provide an overview of the adagrasib clinical data presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting and the Company’s broader lung cancer strategy, including in earlier lines of therapy.

Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

Central Nervous System (CNS) Metastases in KRAS-Mutated Lung Cancer

The brain, along with the bone, adrenals, and liver are common sites of extra-thoracic metastases in NSCLC.[1]−3 CNS metastases occur in 27−42% of patients with KRASG12C-mutated NSCLC at diagnosis.1,4−6 Additionally, patients with CNS metastases and KRAS-mutated NSCLC may have poor outcomes, with median overall survival ranging of approximately five months. 7-9

About Adagrasib (MRTX849)

Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24–48 hours. Adagrasib is being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.

Mirati has an Expanded Access Program (EAP) for investigational adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, including patients with treated or untreated CNS metastases, in the U.S. Learn more about the EAP at Mirati.com/expanded-access-policy.