On June 27, 2023 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies, reported positive updated data from its Phase 1 study of NKX101 to treat patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) (Press release, Nkarta, JUN 27, 2023, View Source [SID1234632932]). NKX101 is an allogeneic, off-the-shelf cell therapy candidate comprising NK cells derived from healthy donors and engineered to target NKG2D ligands on cancer cells.

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Four of six patients in one dose expansion cohort achieved a best composite complete response (67% CR/CRi rate) after receiving at least one cycle of NKX101. In this cohort, a cycle consisted of three weekly doses of NKX101 at 1.5 billion cells per dose after treatment with fludarabine (Flu) and Ara-C (cytarabine) for lymphodepletion. Ara-C is an established and important drug in the treatment of AML across treatment lines, including first line therapy. Exposure to Ara-C is also known to upregulate NKG2D ligands, potentially increasing sensitivity of cancerous cells to NK-cell mediated killing. Data from the NKX101 study suggest Ara-C has the potential to be an effective agent for lymphodepletion.

"Patients with relapsed or refractory AML have few treatment options, and novel approaches are urgently needed. Traditional chemotherapy is often unable to drive deep remissions in this setting, and many patients cannot tolerate it," said Carlos Bachier, M.D., Medical Director of Research and Cellular Therapy, Sarah Cannon Transplant & Cellular Therapy Program at Methodist Hospital in San Antonio, Texas. "NKX101 following lymphodepletion with fludarabine and Ara-C had encouraging anti-tumor activity in a small number of patients with difficult to treat relapsed/refractory AML. This activity, together with its tolerable safety profile, merits further study of NKX101."

"NK cell therapy has long held promise for patients with AML, and these latest results highlight our continued progress towards delivering on that promise with NKX101," said David R. Shook, M.D., Nkarta’s Chief Medical Officer. "While these data are early and in a small number of patients, the response rate exceeds the rate observed with even the latest approved agents and highlights the potential advantages of lymphodepletion using Flu/Ara-C."

Nkarta expects to enroll 12 to 20 additional patients in the expansion cohort using Flu/Ara-C lymphodepletion of the Phase 1 clinical trial and provide a clinical update in the first half of 2024. Nkarta also plans to introduce protocol changes intended to standardize criteria for retreatment and consolidation and simplify study logistics for enrolled patients.

Evaluating NKX101 in r/r acute myeloid leukemia
NKX101 is an allogeneic, cryopreserved, off-the-shelf cancer immunotherapy candidate that uses donor-derived NK cells engineered to target NKG2D ligands on cancer cells. NKX101 is being evaluated in a dose-escalation Phase 1 study as a multi-dose, multi-cycle cellular therapy in patients with r/r AML. As of June 10, 2023, a total of 36 patients with r/r AML were enrolled, compared to 17 at the previous update of April 21, 2022.

Thirty patients with r/r AML were treated with NKX101 after lymphodepletion with fludarabine and cyclophosphamide (Flu/Cy), through dose finding and a separate dose expansion cohort. The majority (17/30, 57%) of patients had poor risk disease. The patients in these cohorts were heavily pre-treated, with 2 median lines of therapy (range 1-12) and 27/30 (90%) having been treated with venetoclax.

A separate, expansion cohort enrolled 6 patients who received lymphodepletion with Flu/Ara-C followed by 3 weekly doses of NKX101 at 1.5 billion cells per dose. This cohort included 5/6 (83%) patients with poor risk disease and other additional high-risk clinical features such as early relapse after allogeneic hematopoietic cell transplant (HCT) and chemo-refractory disease. The patients in this cohort were also heavily pre-treated, with 2 median lines of therapy (range 1-3) and all having been previously treated with venetoclax-containing regimens. Today’s announcement is the first time that results from the Flu/Ara-C cohort are being presented.

Safety in NKX101
NKX101 was well tolerated. No dose-limiting toxicities were observed across all cohorts. The safety profile of NKX101 was consistent across both lymphodepletion regimens. The emerging safety profile of NKX101 is positively differentiated from those of many cell therapies.

In patients with r/r AML that received lymphodepletion with Flu/Cy (Table 1), limited CAR T-like toxicities were observed, including 5 (12%) ≤grade 2 infusion reactions, 5 (12%) cases of ≤grade 2 cytokine release syndrome (CRS), 1 case of grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS), and no graft-versus-host disease (GvHD). The most common higher-grade adverse events were myelosuppression – a condition resulting in fewer red blood cells, white blood cells and platelets, as well as infection, which are common in this patient population post lymphodepletion.

Safety Table 1 – Patients treated with fludarabine / cyclophosphamide lymphodepletion

Grade 3+ AEs in ≥10% of patients Total (n=30)​​
Hematologic Events​ ​
Thrombocytopenia​ 18 (60%)​​
Anemia​ 16 (53%)
Neutropenia​ 13 (43%)​​
Febrile neutropenia ​ 8 (27%) ​
White blood cell count decreased​ 5 (17%)​
Leukocytosis​ 4 (13%)​
Infections​ ​
Pneumonia​ 3 (10%)​​
Other​ ​
Hypoxia​^​ 4 (13%)​​
Fatigue​ 3 (10%)​
Hypotension 3 (10%)

Treatment emergent adverse events regardless of relationship based on interim data from open clinical database as of 10 June 2023 ​
^ In the setting of febrile neutropenia/pneumonia

In patients with r/r AML in the expansion cohort using Flu/Ara-C lymphodepletion (Table 2), there were no observations of CRS, ICANS or GvHD of any grade. Myelosuppression and infection remained the most common higher-grade adverse events. However, there were no >grade 3 infections, and no treatment-associated fatalities.

Safety Table 2 – Patients treated with fludarabine / Ara-C lymphodepletion

Grade 3+ AEs in >1 patient Total (n=6)​​
Hematologic Events​ ​
Anemia​ 3 (50%)
Febrile neutropenia​ 3 (50%)​​
Neutropenia ​ 3 (50%) ​
Thrombocytopenia 2 (33%)
Lymphocyte count decreased​ 2 (33%)​
WBC decreased 2 (33%)​
Infections​ ​
Sepsis 3 (50%)​​

Clinical Activity in NKX101
In patients with r/r AML that received Flu/Ara-C lymphodepletion, 4 of 6 achieved CR/CRi (67% CR/CRi rate) and 3 of 6 achieved a complete response with hematologic recovery (50% CR rate). Two of the 4 reported complete responses were MRD (measurable residual disease) negative. MRD negativity is broadly viewed as an important quantitative measure of disease burden in AML and is associated with increased disease-free survival and decreased risk of recurrence. One patient with MRD positive CR underwent allogeneic HCT and remains in CR at 4 months. Another patient with CR has no detectable disease by flow cytometry and additional MRD testing is pending. Flu and Ara-C are often combined with other chemotherapies, such as idarubicin and mitoxantrone in r/r AML, and such combinations (e.g. FLAG-Ida) have been used as a part of comparator arms in multiple registrational studies, with CR rates between 10-12%.

In patients with r/r AML that received Flu/Cy lymphodepletion, and the highest doses of NKX101 (3 weekly doses at 1 billion or 1.5 billion cells per dose), 4 of 18 achieved CR/CRi (22% CR/CRi rate) and 3 of 18 achieved a complete response with hematologic recovery CR (17% CR rate). There were no CRs at the lower doses of NKX101.

Conference Call Information
Nkarta management will discuss the NKX101 results on Tuesday, June 27, at 8:00 a.m. ET. To access the live webcast, please register online on the Investors section of Nkarta’s website: View Source An archived webcast and accompanying slides will be available on the Company’s website approximately two hours after the event.

About NKX101
NKX101 is an allogeneic, cryopreserved, off-the-shelf cancer immunotherapy candidate that uses natural killer (NK) cells derived from the peripheral blood of healthy donors. It is engineered with a chimeric antigen receptor (CAR) targeting NKG2D ligands on tumor cells. NKG2D, a key activating receptor found on naturally occurring NK cells, induces a cell-killing immune response through the detection of stress ligands that are widely expressed on cancer cells. NKX101 is also engineered with a membrane-bound form of interleukin-15 (IL15) for greater persistence and activity without exogenous cytokine support. To learn more about the NKX101 clinical trial in adults with AML, please visit ClinicalTrials.gov.

About the NKX101 Trial
This Phase 1 clinical trial evaluates the safety and anti-tumor activity of NKX101 as a multi-dose, multi-cycle cellular therapy following lymphodepletion in patients with r/r AML. Patients must have received at least one prior therapy, and patients diagnosed with a disease mutation must have received a targeted therapy, where approved.

Patients in the NKX101 Phase 1 trial received either fludarabine / cyclophosphamide lymphodepletion or fludarabine /Ara-C lymphodepletion followed by NKX101. Patients received doses of 100 million, 300 million, 1 billion or 1.5 billion NK cells three times in the 3-dose regimen, or doses of 150 million or 1.5 billion NK cells two times in the 2-dose regimen. Based on tumor response and tolerability assessment, patients were eligible to receive additional treatment cycles. Disease assessment was performed by investigator review according to the ELN response criteria.

On June 27, 2023 Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of medications to treat severe endocrine, oncologic, metabolic and neurological disorders by modulating the effects of the hormone cortisol, reported publication of the final analysis from its Phase 2 trial evaluating its proprietary cortisol modulator, relacorilant, in women with platinum-resistant ovarian cancer in the Journal of Clinical Oncology (JCO), the premiere journal of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Press release, Corcept Therapeutics, JUN 27, 2023, https://ir.corcept.com/news-releases/news-release-details/journal-clinical-oncology-publishes-results-corcepts-phase-2 [SID1234632930]).

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The publication is titled Relacorilant + Nab-Paclitaxel in Patients with Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study and can be accessed at the following link: View Source

In the trial, patients who received relacorilant orally the day before, the day of and the day after their nab-paclitaxel infusion ("intermittent dosing") experienced a 34 percent reduction in risk of disease progression (median PFS=5.6 vs. 3.8 months, HR 0.66, P=0.038), responded to treatment longer (median DoR=5.6 vs. 3.7 months, HR 0.36, P=0.006) and had a 33 percent reduction in risk of death (median OS=13.9 vs. 12.2 months, HR 0.67, P=0.066) compared to patients who received nab-paclitaxel alone. Adverse events were comparable across the study arms.

PFS and OS benefits were exhibited across multiple subgroups of patients. Patients who would have met the eligibility requirements for Corcept’s confirmatory Phase 3 ROSELLA trial did especially well. A post-hoc analysis showed that patients who had received prior bevacizumab, did not have primary platinum-refractory disease and who had received no more than three prior lines of therapy experienced a 62 percent reduction in risk of death (median OS=17.9 vs. 12.6 months, HR 0.38, P=0.011) compared to similar patients who received nab-paclitaxel alone.

"Outcomes for patients with platinum-resistant ovarian cancer are poor and treatment options are limited," said first author of the publication Nicoletta Colombo, MD, PhD, Associate Professor, Obstetrics and Gynecology, University of Milan-Bicocca, Director, Ovarian Cancer Center, and Chair, Program of Gynecology, European Institute of Oncology, IRCCS, Milan Italy. "The benefits experienced by patients in the intermittent dosing group are meaningful especially given the simple, oral dosing and favorable safety profile of relacorilant. We are on the cusp of developing an entirely new way to treat this serious disease."

"We are excited by the data from our Phase 2 trial and enthusiastic the results have been published in the Journal of Clinical Oncology. Our single goal is to replicate the great results seen in our phase 2 trial," said Bill Guyer, PharmD, Corcept’s Chief Development Officer. "We believe relacorilant has the potential to become a new standard of care for all patients with platinum-resistant ovarian cancer."

About Platinum-Resistant Ovarian Cancer

Ovarian cancer is the fifth most common cause of cancer death in women. Patients whose disease returns less than six months after receiving platinum-containing therapy are described as having "platinum-resistant" disease. In the United States, approximately 20,000 women with platinum-resistant disease are candidates to start a new therapy each year. There are few treatment options and median overall survival following recurrence of disease is typically 12 months or less with single-agent chemotherapy.

On June 26, 2023 Coherus BioSciences, Inc. ("Coherus" or the "Company", Nasdaq: CHRS), reported that effective June 20, 2023, the compensation committee of the Company’s board of directors granted options to purchase an aggregate of 48,000 shares of the common stock of the Company to six newly hired employees with a per share exercise price of $3.84, the closing trading price on the grant date (Press release, Coherus Biosciences, JUN 27, 2023, View Source [SID1234632929]).

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The stock options were granted pursuant to the Coherus BioSciences, Inc. 2016 Employment Commencement Incentive Plan, which was approved by the Company’s board of directors in June 2016 under Rule 5635(c)(4) of the Nasdaq Global Select Market for equity grants to induce new employees to enter into employment with the Company.

On June 27, 2023 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage precision oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with genetically defined cancers, reported initial clinical data from the dose escalation portion of the Phase 1 clinical study of BDTX-1535 (Press release, Black Diamond Therapeutics, JUN 27, 2023, View Source [SID1234632928]). BDTX-1535 is an investigational fourth-generation epidermal growth factor receptor (EGFR) MasterKey inhibitor being developed for the treatment of non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM). The new data from the dose escalation portion of the Phase 1 study demonstrated clinical proof of activity of BDTX-1535 in NSCLC patients harboring both acquired resistance and intrinsic driver EGFR mutations.

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"These initial safety and clinical activity data support the continued development of BDTX-1535 as a potential first and best-in-class treatment option for osimertinib-resistant NSCLC patients. Importantly, BDTX-1535 is the first EGFR TKI to show radiographic responses across NSCLC patients whose cancers are driven by diverse mutation families including acquired resistance mutations after osimertinib therapy, as well as in patients whose cancers are driven by classical and intrinsic driver mutations, providing clinical validation for our MasterKey approach of targeting families of mutations with a single drug," said Sergey Yurasov, M.D., Ph.D., Chief Medical Officer of Black Diamond Therapeutics. "With a favorable tolerability profile in dose escalation, a long half-life to support once-daily dosing and ease of administration, we believe that BDTX-1535 has the potential to become an important treatment option for patients suffering from EGFR-mutated NSCLC. With these data in hand, we look forward to working with the FDA to define our recommended Phase 2 dose selection strategy and, ultimately, discussing a path to potential accelerated approval in NSCLC patients with newly diagnosed and recurrent intrinsic and acquired resistance EGFR mutations."

"Intrinsic and acquired resistance to osimertinib remains a significant challenge for patients with EGFR-mutant lung cancers. There is a large unmet need to personalize therapies based on acquired EGFR resistance mechanisms post treatment with osimertinib but also an equally important unmet need to address intrinsic resistance, with a focus on EGFR mutation subtypes that do worse with current therapies such as EGFR L858R or atypical EGFR mutations such as EGFR exon 18 mutations. That is why a fourth-generation EGFR TKI that addresses intrinsic and acquired resistance by effectively targeting these EGFR alterations – combined with ease of administration and brain penetrance – may be an impactful treatment option for patients. I am eager to see BDTX-1535 continue to advance in the clinic," said Helena Yu, M.D., Associate Attending Physician at Memorial Sloan Kettering Cancer Center.

BDTX-1535 Phase 1 Study Design

This Phase 1 first-in-human, open-label clinical trial of BDTX-1535 consists of dose escalation followed by dose expansion cohorts. The dose escalation part is based on a Bayesian Optimal Interval adaptive design to evaluate the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of BDTX-1535 in adult patients with either advanced/metastatic NSCLC harboring EGFR mutations with or without central nervous system (CNS) disease, or recurrent GBM expressing EGFR alterations. Following the dose escalation portion, the study includes several disease specific expansion cohorts to assess objective response rate (ORR), CNS ORR and progression-free survival and further evaluate safety, tolerability and PK.

Initial Phase 1 Dose Escalation Data

As of the data cutoff date of May 20, 2023, a total of 51 patients (24 patients with recurrent EGFR+ NSCLC and 27 patients with recurrent GBM with EGFR alterations) were treated with BDTX-1535 in the dose-escalation portion of the Phase 1 clinical trial at seven dose levels ranging from 15mg to 400mg once-daily (QD). NSCLC patients (n=24) were heavily pretreated with a median of two prior therapies (range 1-9); all patients received prior treatment with EGFR TKI with the majority receiving osimertinib (79%) as first- or second-line treatment, 67% of patients receiving prior chemotherapy, and 42% of patients receiving prior anti-angiogenesis drug or checkpoint inhibitors. All glioblastoma patients had a recurrent disease after standard of care surgery, radiation and chemotherapy. The Company will provide a clinical update on BDTX-1535 Phase 1 dose escalation data in recurrent GBM patients in the fourth quarter of 2023.

The BDTX-1535 PK profile obtained during dose escalation in NSCLC and GBM patients showed a linear increase in exposure with an average half-life of approximately 15 hours that supports a daily dosing schedule with sufficient and sustained steady state target mutation coverage achieved at 100 mg QD dose level and above.
BDTX-1535 was generally well tolerated by NSCLC and GBM patients and the overall safety profile was consistent with the EGFR tyrosine kinase inhibitor (TKI) class of drugs. The most common drug-related adverse events were mild to moderate rash, diarrhea, stomatitis, paronychia, nausea and fatigue. No patients experienced dose limiting toxicity at 15-200 mg QD doses. One of 15 patients treated at the 300 mg QD dose experienced dose limiting diarrhea and 5 of 12 patients at the 400 mg QD dose experienced dose limiting toxicity (diarrhea, 2 patients; rash, stomatitis, fatigue and decreased appetite, 1 patient each). No unexpected safety signal was identified during dose escalation.
Based on additional data updates as of June 16, 2023, 5 of 12 NSCLC patients in a subgroup, who had measurable disease at study start, and underwent post baseline tumor assessment by RECIST1.1, demonstrated radiographic confirmed partial response (PR). One additional patient demonstrated unconfirmed PR awaiting confirmation, while the remaining six patients had stable disease.
Confirmed PRs were observed in NSCLC patients with a wide range of EGFR mutations including classical and intrinsic driver mutations and acquired C797S resistance mutation, as well as complex mutations that include a combination of classical, intrinsic, and acquired resistance mutations. Radiographic improvement of CNS metastasis was documented in 2 NSCLC patients.
Based on emerging PK, safety, tolerability and radiographic response data, enrollment will commence at the BDTX-1535 200 mg QD dose in two expansion cohorts of NSCLC patients with acquired resistance or intrinsic driver mutations who received up to two prior lines of therapy including a third-generation EGFR TKI. Additional doses may be further evaluated after review of the totality of dose escalation data during a meeting with the U.S. Food and Drug Administration (FDA) later in 2023. The objective of expansion cohorts will be ORR by RECIST 1.1 and durability of response to support future discussion with the FDA of a potential accelerated approval path in EGFR-mutated NSCLC. In addition, BDTX plans to open an expansion cohort in newly diagnosed NSCLC patients with intrinsic driver mutations after discussion with the FDA.
Black Diamond anticipates the following key milestones for BDTX-1535:

Initiation of the dose expansion cohorts of NSCLC patients with EGFR acquired resistance and intrinsic driver mutations after progression on third generation EGFR TKI with the objective of ORR by RECIST 1.1 in the second half of 2023
Presentation of the full BDTX-1535 dose escalation data in NSCLC at a medical conference in the fourth quarter of 2023
Meeting with the FDA in the fourth quarter of 2023 to align on dosing strategy to enable a potential accelerated approval pathway in NSCLC
Initiation of an expansion cohort in newly diagnosed NSCLC patients with intrinsic driver mutations after discussion with the FDA
Clinical update on BDTX-1535 Phase 1 dose escalation data in recurrent GBM patients in the fourth quarter of 2023
Conference Call Information

Black Diamond will host a conference call and webcast on Tuesday, June 27, 2023, at 8:00 a.m. ET to discuss the initial results from the Phase 1 dose escalation study of BDTX-1535 in patients with NSCLC. The webcast may be accessed online here or by visiting the Events page in the Investors section of the Company’s website at www.blackdiamondtherapeutics.com.

A replay of the webcast will be available for 30 days on the Investors section of Black Diamond’s website.

On June 27, 2023 Biodesix, Inc. (Nasdaq: BDSX), a leading data-driven diagnostic solutions company with a focus in lung disease, reported that the large multi-center observational registry study INSIGHT (Clinical Effectiveness Assessment of VeriStrat Testing and Validation of Immunotherapy Tests in NSCLC Subjects) (NCT03289780) has completed enrollment of 5,000 patients with non-small cell lung cancer (NSCLC) (Press release, Biodesix, JUN 27, 2023, View Source [SID1234632927]). The study was designed to further validate the utility of the VeriStrat test, a novel predictive and prognostic blood-based host immune classifier, and its ability to support treatment decisions for patients with NSCLC across different therapeutic approaches.

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"The INSIGHT study gives us a unique opportunity to examine real world treatment patterns for lung cancer, the deadliest of all cancers, in the context of patients’ immune response," said Dr. James Jett, co-Chief Medical Officer at Biodesix. "Five-year survival for patients with non-small cell lung cancer is approximately 25 percent, but now we are seeing that with use of this proteomic test, we are able to identify treatment options, particularly those utilizing Immune Checkpoint Inhibitors in addition to standard chemotherapy, that may extend overall survival in select groups of patients."

Results from prior analyses of the INSIGHT study demonstrated that the VeriStrat test stratifies immune checkpoint inhibition (ICI) treatment response in patients with advanced NSCLC. This data demonstrated that those classified as Host Immune Classifier Cold (HIC-C), also known as VeriStrat Poor, had superior median overall survival when receiving ICI plus chemotherapy versus ICI alone, independent of PD-L1 status.

A recent analysis from this study has been accepted for presentation at the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in Singapore in September 2023. Future analyses of the INSIGHT study are planned in 2024, as monitoring of patient outcomes continues.