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]).

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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.

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"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.

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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.

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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%.

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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.

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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.

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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.

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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:

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

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

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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.

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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.

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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.

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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]).

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On October 13, 2023 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported updated preliminary data from the Phase 1 dose-escalation portion of its ongoing ALKOVE-1 Phase 1/2 clinical trial of NVL-655 for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors (Press release, Nuvalent, OCT 13, 2023, View Source [SID1234635952]). These data will be presented today at the 35th AACR (Free AACR Whitepaper)-NCI-EORTC (ANE) Symposium in Boston, Massachusetts.

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NVL-655 is a novel brain-penetrant ALK-selective tyrosine kinase inhibitor (TKI) created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, brain metastases, and off-target central nervous system (CNS) adverse events associated with tropomyosin receptor kinase (TRK) inhibition that may limit the use of currently available ALK TKIs.

"Significant advancements have been made with the development of three generations of ALK TKIs, and the five ALK inhibitors that are currently FDA-approved provide important treatment options for patients with advanced ALK fusion-positive cancers. However, some limitations remain with the available therapies, ranging from association with TRK-related neurologic adverse events that can limit adequate coverage of ALK single resistance mutations to the emergence of refractory compound mutations following sequential treatment with ALK TKIs," said presenting investigator Jessica J. Lin, M.D., Assistant Professor of Medicine, Harvard Medical School and Attending Physician, Mass General Cancer Center. "These preliminary data support the potential for NVL-655 as an ALK-selective inhibitor that may combine, for the first time, potent and selective targeting of diverse ALK fusions and secondary ALK resistance mutations, including single and compound mutations involving G1202R and I1171N, brain penetrance, and the avoidance of TRK inhibition that can be dose limiting."

As of the enrollment and data cut-off date of August 8, 2023 for the preliminary data, 93 patients have been enrolled in the Phase 1 portion of the ALKOVE-1 trial across six evaluated dose levels of NVL-655 ranging from 15 mg once daily (QD) to 200 mg QD. Enrollment in the Phase 1 portion of the trial is ongoing.

Preliminary activity data as of the cut-off date were available from 51 heavily pre-treated response-evaluable NSCLC patients. The objective response rate (ORR) by RECIST 1.1 was 39% (20/51) of patients treated at all doses, of which all were partial responses (4 pending confirmation). In the subset of 41 patients treated at dose levels of 50 mg QD or higher, the ORR was 44% (18/41).

To evaluate key target characteristics of NVL-655, activity was examined in subgroups of the 51 response-evaluable patients treated at all doses, including:

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Patients with any history of CNS metastases (ORR 52%, 15/29);

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Patients with any ALK resistance mutation (ORR 54%, 15/28), including those with compound ALK mutations (ORR 56%, 9/16) and those with ALK G1202R single or compound mutations (ORR 71%, 12/17);

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The most heavily pre-treated of patients, after receiving ≥3 prior ALK TKIs including at least one 2nd generation (2G) ALK TKI (alectinib, brigatinib, or ceritinib) plus lorlatinib, and prior chemotherapy (ORR 42%, 8/19); and,

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Lorlatinib-naïve patients who had received at least one 2G +/- 1G ALK TKI (ORR 71%, 5/7).

Preliminary pharmacokinetic (PK) analyses were available for dose levels 15 mg QD to 150 mg QD. Treatment with NVL-655 resulted in exposure above target efficacy thresholds in both the periphery and in the CNS. These preliminary PK data suggest that dose levels of 50 mg QD and above may provide increased coverage of single and compound mutations in the CNS. Preliminary pharmacodynamic analysis showed that NVL-655 induced clearance of diverse ALK resistance mutation alleles across a wide dose range.

As of the cut-off date for the preliminary data, 67% (34/51) of response-evaluable patients remained on treatment with NVL-655 with duration of treatment up to 12 months (median duration of treatment of 3.4 months). All patients with tumor response continued on treatment without disease progression. NVL-655 was well-tolerated with a preliminary safety profile that was favorable and consistent with its ALK-selective, TRK sparing design.

"We are excited to present the first look at the safety and clinical activity of NVL-655 from our ALKOVE-1 clinical trial, which we believe supports the potential for NVL-655 to address each key area of its desired target product profile," said Christopher Turner, M.D., Chief Medical Officer of Nuvalent. "Across a wide dose range, NVL-655 demonstrated activity in a heavily pre-treated patient population that uniquely includes patients in the post-lorlatinib setting, with a favorable preliminary safety profile consistent with its ALK-selective, TRK sparing design. Importantly, all patients with tumor response remained on treatment without disease progression as of the data cut-off date, suggesting the potential for durable responses even in this late line population."

Dr. Turner continued, "Ultimately, we view the ability to keep patients on therapeutically relevant dose levels as a key indicator of the potential for NVL-655 to drive clinically meaningful durable responses when used earlier in the treatment paradigm. In earlier lines of therapy, potent activity against ALK as well as single or compound ALK resistance mutations in both the periphery and the brain has the potential to delay or prevent the emergence of both treatment resistance and CNS progression. Furthermore, selective inhibition of wild-type ALK and its resistance variants may minimize TRK-related CNS adverse events and other off-target toxicities that can be dose limiting. We believe that the preliminary characteristics of NVL-655 observed in this heavily pre-treated patient population support its opportunity as a potential best-in-class therapy that can move up the treatment paradigm to deliver deep and durable responses for patients with ALK-positive cancers."

"With today’s data, Nuvalent has presented preliminary proof-of-concept data for both of its novel parallel lead programs in ROS1 and ALK-positive cancers in just over 5 years since the company’s inception," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "We believe this achievement is a testament to the dedication of the Nuvalent team, and to our approach of collaboration with leading physician-scientists, identification of medical needs stemming from the limitations of existing therapies, and focused application of our innovative chemistry and deep expertise in structure-based drug design to develop precisely targeted therapies according to well-defined target product profiles."

Dr. Porter continued, "Most importantly, we recognize that this achievement is made possible by the patients, caregivers, and investigators who are participating in the ALKOVE-1 trial and offer our sincere gratitude. We look forward to discussions with investigators and regulators on the selection of a recommended Phase 2 dose (RP2D) and the transition to the planned Phase 2 portion of ALKOVE-1 for patients with lorlatinib-naïve and lorlatinib-treated ALK-positive NSCLC. We also look forward to using the preliminary data to guide discussions with physicians regarding potential development strategies for patients with TKI-naïve ALK-positive NSCLC as we work towards our goal of bringing new treatment options to all patients with ALK-positive cancers."

NVL-655 First-in-Human Preliminary Phase 1 Data

NVL-655 is currently being evaluated in the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626). The Phase 1 dose escalation portion is enrolling ALK-positive NSCLC patients who have previously received at least one ALK TKI and patients with other ALK-positive solid tumors who have been previously treated with at least one prior systemic anticancer therapy. The primary objectives are to determine the RP2D and if applicable, the maximum tolerated dose (MTD) of NVL-655 in patients with ALK-positive solid tumors. Additional objectives include characterization of the overall safety, tolerability, and pharmacokinetic profile, and evaluation of the preliminary anti-tumor activity and intracranial activity of NVL-655.
As of the enrollment and data cut-off date of August 8, 2023 for the preliminary data, 93 patients were enrolled in the Phase 1 portion of the ALKOVE-1 trial, of which 91 patients had ALK-positive NSCLC and 58% (54/93) had a history of CNS metastases.

The patient population was heavily pre-treated:

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100% (93/93) had received a 2G ALK TKI or lorlatinib;

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77% (72/93) had received two or more ALK TKIs, including a 2G ALK TKI and lorlatinib;

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44% (41/93) had received three or more ALK TKIs, including a 2G ALK TKI and lorlatinib; and,

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46% (43/93) had an identified secondary ALK mutation, including 26% (24/93) with any compound ALK mutation.

Preliminary Activity Analysis

As of the cut-off date for the preliminary data, patients were treated in six NVL-655 dose cohorts of 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg QD. Fifty-one patients with NSCLC were response-evaluable by investigator assessment with duration of treatment up to 12 months (median duration of treatment of 3.4 months).

Key findings include early anti-tumor activity in ALK-positive NSCLC patients, including partial responses (RECIST 1.1) in:

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Heavily pre-treated patients: An ORR of 39% (20/51) was observed in response-evaluable patients, and all patients with tumor response continued on treatment without disease progression as of the data cut-off date.

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For dose levels of 50 mg or greater, which may provide increased coverage of single and compound mutations in the CNS, an ORR of 44% (18/41) was observed.

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In patients who have likely exhausted all available treatment options (≥3 prior ALK TKIs including a 2G ALK TKI and lorlatinib), the observed ORR was 40% (10/25) regardless of prior chemotherapy and 42% (8/19) with prior chemotherapy.

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Patients with ALK single or compound resistance mutations: An ORR of 54% (15/28) was observed in patients with any ALK resistance mutation, including an ORR of 56% (9/16) in patients with compound ALK mutations, and an ORR of 71% (12/17) in patients with ALK G1202R single or compound mutations.

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Patients with CNS metastases: An ORR of 52% (15/29) was observed in patients with any history of CNS metastases. All patients with tumor response who had a history of CNS disease continued on treatment without CNS progression.

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Lorlatinib-naïve patients: Of patients who received at least one 2G +/- 1G ALK TKI and had not previously received lorlatinib, 5 of 7 (71%) responded.

Preliminary Safety, Pharmacokinetic, and Pharmacodynamic Analysis

A favorable preliminary safety profile was observed with NVL-655 treatment in the 93 patients enrolled across the dose-escalation portion of ALKOVE-1, consistent with an ALK-selective, TRK-sparing design. Most treatment-related adverse events (TRAEs) were low-grade and manageable, with the highest incidence of TRAEs being ALT increase (19%, 18/93 any grade; 6%, 6/93 ≥ Grade 3), AST increase (18%, 17/93 any grade; 4%, 4/93 ≥ Grade 3), and nausea (10%, 9/93 of which all were Grade 1 or 2). TRAEs requiring dose modification were infrequent, with 2% (2/93) discontinuations and 5% (5/93) dose reductions. There was one dose-limiting toxicity of transient asymptomatic Grade 4 CPK increase at the 200 mg QD dose level. An MTD was not reached, and the preliminary overall safety profile was consistent with avoidance of TRK-related neurotoxicities.

The observed favorable preliminary safety profile allowed for achievement of NVL-655 exposure levels above target CNS efficacy thresholds for ALK, ALK single and compound G1202R mutations, and other recalcitrant ALK single mutations such as I1171N. Favorable PK and low intra-cohort patient PK variability were observed, with dose-proportional exposure and a half-life that is supportive of once daily dosing. This preliminary PK data suggest that dose levels of 50 mg QD or greater may provide increased coverage of single and compound mutations in the CNS.

Preliminary pharmacodynamic findings by centrally confirmed ctDNA analysis showed that treatment with NVL-655 induced clearance of diverse ALK resistance mutation alleles across a wide dose range. Notably, 100% clearance was observed in 14 of 16 patients with centrally confirmed single or compound ALK G1202R or I1171X (X = N or T) mutations, of which 13 had received prior lorlatinib.

Combined with the favorable preliminary activity observed as of the data cut-off date, these data suggest that NVL-655 has opportunity as a potential best-in-class therapy that may be able to move up the treatment paradigm for patients with ALK-positive NSCLC.

The ALKOVE-1 clinical trial is continuing to enroll patients in the Phase 1 portion of the trial and is focused on further characterizing the safety, PK, and pharmacodynamic profiles, determining the RP2D, and if applicable, the MTD of NVL-655. Upon RP2D selection, the trial is designed to transition directly into the Phase 2 portion, which will evaluate the safety and activity of NVL-655 in several expansion cohorts of patients defined based on the number and type of prior anti-cancer therapies they have received. The Phase 2 cohorts are intended to support potential registration in patients with ALK-positive NSCLC who are both lorlatinib-naïve and lorlatinib-treated.

In addition to the planned Phase 2 cohorts, Nuvalent intends to use these preliminary data in patients with heavily pre-treated ALK-positive NSCLC to guide discussions with physicians that will inform development strategies in TKI-naïve ALK-positive NSCLC.

Webcast and Conference Call Information

A conference call with management will be held today at 8:00 am EDT. To access the call, please dial +1 (866) 652-5200 (domestic) or +1 (412) 317-6060 (international) at least 10 minutes prior to the start time and ask to be joined to the Nuvalent call. Accompanying slides and a live video webcast will be available in the Investors section of the Nuvalent website at https://investors.nuvalent.com/events. A replay and accompanying slides will be archived on the Nuvalent website for 30 days.

About NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R / L1196M ("GRLM"), G1202R / G1269A ("GRGA"), or G1202R/L1198F ("GRLF"). NVL-655 has been designed for CNS penetrance to improve treatment options for patients with brain metastases. NVL-655 has been observed in preclinical studies to selectively inhibit wild-type ALK and its resistance variants over the structurally related tropomyosin receptor kinase (TRK) family to potentially avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and drive more durable responses for patients. NVL-655 is currently being investigated in the ALKOVE-1 clinical trial (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors.