On June 1, 2024 Bristol Myers Squibb (NYSE: BMY) reported results from the Phase 3 KRYSTAL-12 study evaluating KRAZATI (adagrasib) compared to standard of care chemotherapy in patients with locally advanced or metastatic KRASG12C -mutated non-small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy (Press release, Bristol-Myers Squibb, JUN 1, 2024, View Source [SID1234643923]). At a median follow-up of 9.4 months, KRAZATI demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), the study’s primary endpoint, as assessed by Blinded Independent Central Review (BICR) compared to docetaxel (HR: 0.58; [95% CI, 0.45-0.76]; P <0.0001). Median PFS was 5.5 months for KRAZATI compared to 3.8 months for docetaxel. Overall response rate (ORR) as assessed by BICR was also significantly higher with KRAZATI compared to docetaxel (32% vs 9%; odds ratio, 4.68; P < 0.0001). The median duration of response (mDOR) was 8.31 months (95% CI, 6.05–10.35) versus 5.36 months (95% CI, 2.86–8.54), respectively.

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KRAZATI demonstrated intracranial response among patients with central nervous system (CNS) metastases at baseline, with a response rate per BICR that was more than double that observed with docetaxel (24% with KRAZATI vs. 11% with docetaxel).

The KRYSTAL-12 study remains ongoing to assess the additional key secondary endpoint of overall survival.

No new safety signals were identified for KRAZATI, and the safety data were consistent with the known safety profile. Treatment-related adverse events (TRAEs) of any grade were reported in 94% of patients treated with KRAZATI and 86.4% with docetaxel. Grade ≥3 TRAEs occurred in 47% and 46% of patients, respectively.

These data will be presented in a late-breaking oral presentation during the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 1 at 1:27 p.m. CDT (Abstract LBA8509).

"Approximately 14% of all patients with advanced non-small cell lung cancer carry the KRASG12C mutation, impacting thousands of people worldwide," said Tony Mok, M.D., Chairman of the Department of Clinical Oncology and Li Shu Fan Medical Foundation Professor of Clinical Oncology of the Faculty of Medicine at The Chinese University of Hong Kong (CU Medicine). "These results from the Phase 3 KRYSTAL-12 study reinforce adagrasib as a targeted option for patients with KRASG12C -positive lung cancer after failing standard first-line treatment."

"The accelerated approval of KRAZATI from the FDA in 2022 was welcome news for patients with KRASG12C -mutated locally advanced or metastatic NSCLC. These confirmatory results further support KRAZATI as an efficacious, targeted treatment option for these patients," said Abderrahim Oukessou, M.D., vice president, global program lead, KRAZATI, Bristol Myers Squibb. "We look forward to further sharing these results, while also continuing to evaluate KRAZATI in other advanced KRASG12C -mutated solid tumors."

In addition to KRASG12C -mutated NSCLC, KRAZATI and KRAZATI-based combinations have shown encouraging, meaningful benefit in Phase 2 clinical trials across several tumors, including advanced colorectal cancer, pancreatic cancer, and other solid tumors.

Bristol Myers Squibb thanks the patients and investigators involved in the KRYSTAL-12 clinical trial.

This study was funded by Mirati Therapeutics, Inc., a Bristol Myers Squibb company. KRAZATI is a registered trademark of Mirati Therapeutics, Inc., a Bristol Myers Squibb company.

About KRYSTAL-12

KRYSTAL-12 is an open-label, multicenter, randomized Phase 3 study evaluating KRAZATI compared to standard-of-care chemotherapy alone, in patients with KRASG12C -mutated non-small cell lung cancer. The primary endpoint of the study is progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), and safety.

About KRAS G12C – Mutated Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths globally. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer, representing up to 84% of diagnoses. KRASG12C is the most common KRAS mutation in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker of poor prognosis.

About KRAZATI (adagrasib)

KRAZATI (adagrasib) is a 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. KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of non-small cell lung cancer, 3-4% of colorectal cancer, and 1-2% of several other cancers.

In 2022, the U.S. Food and Drug Administration (FDA) granted KRAZATI accelerated approval for treatment of adult patients with KRASG12C -mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

KRAZATI continues to be evaluated as a monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C -mutated solid tumors, including NSCLC and colorectal cancer (CRC).

Please see U.S. Full Prescribing Information for KRAZATI .

INDICATION

KRAZATI is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

GASTROINTESTINAL ADVERSE REACTIONS

In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity
QTC INTERVAL PROLONGATION

KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death
In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are taking medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity
HEPATOTOXICITY

KRAZATI can cause hepatotoxicity
In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% of patients
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity
INTERSTITIAL LUNG DISEASE/PNEUMONITIS

KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or 4, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified
ADVERSE REACTIONS

The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite
FEMALES AND MALES OF REPRODUCTIVE POTENTIAL

Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential
Please see U.S. Full Prescribing Information for KRAZATI .

On June 1, 2024 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer, reported additional data from the Phase 1 dose escalation trial of BDTX-1535 in patients with recurrent glioblastoma (GBM), and initial data from a phase 0/1 "trigger" ("window of opportunity") investigator-sponsored trial at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Black Diamond Therapeutics, JUN 1, 2024, View Source [SID1234643922]). Clinical data from these trials in patients with recurrent GBM demonstrated brain penetrance of BDTX-1535, as well as safety and tolerability data similar to what has been previously described for patients with non-small cell lung cancer (NSCLC). In addition, the Phase 1 trial demonstrated encouraging anti-tumor activity and duration of treatment for patients with previously treated GBM.

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"The Phase 1 dose escalation results in patients with recurrent GBM show promising duration of treatment beyond two to four months typically expected in the recurrent setting, along with good safety and tolerability at therapeutic doses," said Patrick Wen, M.D., Director of The Center for Neuro-Oncology at Dana-Farber Cancer Institute. "Ultimately, the optimal point of intervention with an EGFR TKI may be upon initial diagnosis given the potential loss of EGFR as an oncogenic driver following chemotherapy and radiation."

In the poster titled "Phase 1 Study of BDTX-1535, an Oral 4th Generation Covalent EGFR Inhibitor, in Patients with Recurrent Glioblastoma: Dose Escalation Results," patients with EGFR alterations at initial diagnosis were enrolled upon recurrence. Patients received increasing doses of BDTX-1535 in 21-day cycles to assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. As of the data cutoff date of January 20, 2024:

Safety/tolerability was consistent with BDTX-1535 clinical data in NSCLC previously presented in October 2023 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).

Treatment-related adverse events (TRAEs) were primarily mild to moderate; the most common events included rash, diarrhea, stomatitis, paronychia, nausea, and fatigue.
No grade 3 TRAEs were reported at doses of BDTX-1535 ≤100 mg/day, one grade 3 rash was observed at 200 mg, and no grade 4/5 TRAEs were observed.
Among 19 efficacy evaluable patients, several experienced stable disease with promising durability.

One confirmed partial response was observed and eight patients experienced stable disease.
Five patients remained on BDTX-1535 treatment for ≥4 months, 1 patient for ≥6 months, and 3 patients for ≥10 months.
Longest duration of treatment was a patient who remained on therapy beyond 16 months.
Longer duration of treatment with BDTX-1535 appeared to be associated with a shorter duration of prior treatment with temozolomide.
A second poster titled "A Phase 0/1 ‘Trigger’ Trial of BDTX-1535 in Recurrent High-Grade Glioma (HGG) Patients with EGFR Alterations or Fusions," is an investigator-sponsored trial conducted at the Ivy Brain Tumor Center in Arizona. Patients with recurrent HGG with EGFR alterations and/or fusions at initial diagnosis were dosed with either 200mg BDTX-1535 daily for five days prior to brain tumor resection or 400mg administered three times per week prior to resection. A pre-specified PK threshold of 4.1nM unbound drug concentration was established, representing exposure that is 5-fold above the IC50 of BDTX-1535 for EGFR alterations and amplifications found in patients with GBM. Initial results from the trial demonstrated that BDTX-1535 exceeded the pre-specified threshold for drug concentration in the brain tumor tissue. In addition, both dosing regimens were generally well tolerated with expected EGFR-mediated side effects.

"We are very pleased with these initial results from our study showing that BDTX-1535 achieves levels in brain tumor tissue needed to observe a therapeutic effect," said Nader Sanai, M.D., Director of the Ivy Brain Tumor Center. "Clinical activity in these patients with further follow-up could support an additional trial of BDTX-1535 in newly diagnosed patients with confirmed EGFR mutations."

As of the data cutoff date of May 3, 2024, nine patients were evaluable:

BDTX-1535 generally well tolerated and achieved target drug concentration in tumor tissue.

BDTX-1535 was generally well tolerated with no serious adverse events related to BDTX-1535.
Eight of nine (88.9%) patients exceeded the PK threshold of 4.1nM unbound drug concentration, with average unbound drug concentration in Gadolinium (Gd) non-enhancing tumor tissue of 11.9 nM (for the 200mg dose) and 18.8nM (for the 400mg dose).
BDTX-1535 was associated with suppression of EGFR-mediated signaling as determined by several pharmacodynamic markers.
Patients achieving the PK threshold were enrolled in the post-resection component of the study with an update expected in the fourth quarter of 2024.
About BDTX-1535
BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), including classical driver mutations, non-classical driver mutations, and the acquired resistance C797S mutation. BDTX-1535 is a fourth-generation tyrosine kinase inhibitor (TKI) that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. A "window of opportunity" trial of BDTX-1535 in patients with GBM is ongoing (NCT06072586) and a Phase 2 trial is ongoing in patients with NSCLC (NCT05256290).

On June 1, 2024 Genmab A/S (Nasdaq: GMAB, "Genmab") and BioNTech SE (Nasdaq: BNTX, "BioNTech") reported initial data from the ongoing Phase 2 trial (NCT05117242) evaluating acasunlimab (DuoBody-PD-L1x4-1BB), an investigational bispecific antibody also known as GEN1046/BNT311, as monotherapy and in combination with pembrolizumab in patients with PD-L(1)-positive metastatic non-small cell lung cancer ("mNSCLC") who had disease progression following one or more prior lines of anti-PD(L)1-containing treatment (Press release, BioNTech, JUN 1, 2024, View Source [SID1234643921]). The results showed a 12-month overall survival ("OS") rate of 69%, a median overall survival ("mOS") of 17.5 months, and a 30% overall response rate ("ORR") (confirmed ORR 17%) at the time of data cut-off in patients treated with the combination of acasunlimab and pembrolizumab every six weeks. The findings were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Annual Meeting held in Chicago, IL from May 31-June 4, 2024.

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The Phase 2 study randomized a total of 113 patients in three arms, evaluating acasunlimab alone (Arm A) and in combination with pembrolizumab (Arms B and C). The objective response analysis was conducted for 62 centrally confirmed PD-L1-positive efficacy-evaluable patients. The OS was evaluated in all centrally confirmed PD-L1-positive patients (n=80). Arm A showed a mOS rate of 5.5 months, a 50% disease control rate (DCR) and a 31% ORR (confirmed ORR 13%) in patients treated with acasunlimab alone. An 8.6 months mOS, a 59% DCR and a 21% ORR (confirmed ORR 18%) for treatment of acasunlimab in combination with pembrolizumab every three weeks (Arm B) and a 17.5 months mOS, a 75% DCR and a 30% ORR (confirmed ORR 17%) when the combination was administered every six weeks (Arm C). Anti-tumor activity was observed in patients with a tumor proportion score ("TPS") of 1–49% and ≥50%, in patients with <6 months and ≥6 months of previous immune checkpoint inhibitor ("CPI") treatment, and in patients with squamous and non-squamous histology.

Adverse events were consistent with the safety profiles of the individual drugs and treatment related adverse events ("TRAEs") were primarily grade 1 and 2. The most common TRAEs (all grades) in Arm A were asthenia (22.7%), diarrhea (18.2%), nausea (18.2%), anemia (13.6%), and liver-related events (13.6%). In the combination arms (Arms B and C), the most common TRAEs were liver-related events (28.6%, 18.4%), fatigue (21.4%, 8.2%), asthenia (12%, 12.2%), and diarrhea (12%, 10.2%). Overall, a lower incidence of grade ≥3 TRAEs, treatment-related liver-related events and lower discontinuation rates were observed with the combination regimen therapy administered every six weeks. Transaminase elevations were generally asymptomatic and manageable with the administration of steroids and/or treatment delay and resolved more rapidly in patients treated with the combination therapy administered every six weeks.

"We are encouraged by the findings of this ongoing Phase 2 study. The initial results of acasunlimab in combination with pembrolizumab administered every 6 weeks suggest a potential meaningful impact on patients with metastatic non-small cell lung cancer," said Judith Klimovsky, Executive Vice President & Chief Development Officer at Genmab. "We will continue to evaluate these data to inform further development of acasunlimab including a planned Phase 3 trial as we remain committed to investigate acasunlimab as a potential treatment option."

"Most patients with mNSCLC have limited treatment options following progression on first-line checkpoint inhibitor therapy. For these patients, chemotherapy remains the main treatment despite limited efficacy and considerable toxicity," said Prof. Özlem Türeci, M.D., Chief Medical Officer and Co-Founder at BioNTech. "The data of our Phase 2 trial show that the combination of acasunlimab with PDL1-blockade may be a suitable approach in this heavily pretreated patient population."

About the GCT1046-04 Clinical Trial

The GCT1046-04 trial (NCT05117242) is a randomized, open-label trial evaluating the safety and efficacy of acasunlimab in patients with relapsed/refractory metastatic non-small cell lung cancer ("mNSCLC") after treatment with standard of care therapy containing immune checkpoint inhibitor therapy. Patients with stage IV NSCLC with at least one prior line of systemic therapy containing an anti-PD-1/PD-L1 and a tumor PD-L1 expression in ≥1% of the tumor cells are included in the study. The primary endpoint of the trial is the overall response rate ("ORR"). Key secondary endpoints include overall survival ("OS"), progression free survival ("PFS"), time to response ("TTR"), duration of response ("DOR"), and safety. More information on this trial can be found at clinicaltrials.gov.

About Non-small Cell Lung Cancer (NSCLC)

Non-small cell lung cancer ("NSCLC") is the most common type of lung cancer, accounting for about 85% of all reported cases. NSCLC starts in cells that line the airways and can grow into nearby tissues or spread to other parts of the body. NSCLC is often diagnosed at an advanced stage, when it is hard to treat and has a poor prognosis. The survival rate of patients with NSCLC varies depending on the stage at diagnosis.i,ii,iii,The treatment of NSCLC depends on the stage, subtype, and biomarker status of the disease, and may include surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these modalities.

About Acasunlimab (GEN1046/BNT311)
Acasunlimab (GEN1046/BNT311) is an investigational PD-L1x4-1BB bispecific antibody fusing Genmab’s proprietary DuoBody technology platform and BioNTech’s proprietary immunomodulatory antibodies. Acasunlimab is designed to elicit an antitumor response via conditional activation of 4-1BB on T cells and natural killer cells, which is strictly dependent on simultaneous binding of the PD-L1 arm. Acasunlimab is being developed in collaboration by BioNTech and Genmab under a license and collaboration agreement. The candidate is currently being investigated in three clinical trials: (1) a Phase 1/2 safety trial in patients with multiple solid tumors, (2) a Phase 1 dose escalation trial in patients with advanced solid tumors in Japan, and (3) a randomized Phase 2 safety and efficacy trial with acasunlimab as a monotherapy and in combination with pembrolizumab in patients with NSCLC who have failed previous standard of care treatments with immune checkpoint inhibitors. Please visit www.clinicaltrials.gov for more information.

On June 1, 2024 Sairopα, a clinical-stage developer of innovative cancer therapies, reported updated results from its dose-escalation phase of the ongoing Phase 1 study evaluating safety, pharmacokinetics and clinical efficacy of ADU-1604 (anti-CTLA4 antibody) in advanced PD-1 relapsed/refractory melanoma patients at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2024 in Chicago (Press release, Sairopa, JUN 1, 2024, View Source [SID1234643919]).

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Data from the completed dose-escalation study (n=20) in PD-1 relapsed/refractory melanoma patients shows that ADU-1604 is well tolerated at dosages of 25, 75, 225 and 450 mg Q3W, demonstrating a mild safety profile and no dose-limiting toxicities. Early signs of clinical efficacy were observed in three patients (two patients at 225 mg and one patient at 450 mg). Dose-dependent increase of pharmacodynamic biomarkers was detected, including strong increase of CD8+ T-cell proliferation in patients that showed tumor reduction.

The currently ongoing dose-expansion phase will treat an additional 20 patients (n=20) at the recommended Phase 2 dose (RP2D) of 225mg to support potential future combination therapies.