Investigators are evaluating the combination of repotrectinib (TPX-0005) and osimertinib (Tagrisso) for the treatment of patients with advanced or metastatic 

-mutant non–small cell lung cancer (NSCLC) in the phase 1 TOTEM trial (NCT04772235). The study design was presented at the 2022 World Conference on Lung Cancer. 

TOTEM is a single-arm, multicenter trial evaluating repotrectinib in combination with osimertinib in patients with advanced or metastatic 

The study has been initiated and will be conducted across 4 hospitals in Spain.

“Osimertinib has robust efficacy and is the standard first-line treatment for advanced 

-mutant NSCLC. [But] lung cancer cells generate resistance to osimertinib through activation of other TKI signaling pathways,” study authors wrote in the poster.

Repotrectinib is a receptor TKI of ROS1 and TRK that directly competes with ATP binding and inhibits wild-type fusion proteins and fusion proteins harboring resistance. In preclinical assays, the agent has shown potent multi-kinase inhibition against a range of resistance mechanisms including JAK2, SRC, and FAK at clinically relevant concentrations.

“The combination of osimertinib with repotrectinib inhibited Src/FAC/JAK2 in 

-mutant cell lines and abrogated STAT3 and YAP1 signaling with tumor growth inhibition in vitro and in vivo. There was no substantial toxicity in nude mice models,” study authors added. “Based on this evidence and repotrectinib’s unique inhibition affinity for Src, FAC and JAK2, we designed the current trial.”

To be eligible for enrollment, patients must be at least 18 years of age with a diagnosis of locally advanced, unresectable or metastatic NSCLC with local or central determination of 

 exon 18, exon 19, exon 21, or T790M mutation. Patients must have an ECOG performance of 0 or 1 and a creatinine clearance of more than 50 mL/min. Patients with asymptomatic brain metastases are eligible, and treatment with prior chemotherapy, immunotherapy, and TKIs, including osimertinib, is allowed.

The primary objective of the study is to establish the safety and tolerability of repotrectinib across several doses in combination with osimertinib; determine the first cycle of dose-limiting toxicities (DLTs) and the maximum tolerated dose of repotrectinib given in combination with osimertinib; and identify the recommended phase 2 dose (RP2D) of repotrectinib given in combination with osimertinib. The RP2D will be defined as the dose level with less than 33% of patients experiencing a DLT.

Secondary end points include evaluating repotrectinib’s effect on the pharmacokinetics of osimertinib, establishing the pharmacokinetics of the combination, and determining the preliminary efficacy of the combination defined by the objective response rate (ORR), intracranial ORR, duration of response, clinical benefit rate, progression-free survival, and overall survival.

All radiographic efficacy end points will be based on investigator assessment using RECIST v1.1 criteria. Intracranial responses will also be evaluated by RECIST v1.1 criteria.

Investigators will evaluate pharmacodynamic effects and potential predictive biomarkers of response for the combination using serial tumor biopsy and/or blood samples as an exploratory objective. 

The study includes 2 parts: part A is a dose-escalation phase following a 3+3 design including 6 to 18 patients to determine the RP2D. Patients in part A will receive osimertinib monotherapy for 14 days at 80 mg per day, followed by osimertinib in combination with repotrectinib at the assigned dose level of 80 mg or 160 mg once daily, or 160 mg twice daily.

Part B is an expansion phase enrolling 20 to 30 patients who have progressed on osimertinib or first-/second-generation TKIs. Patients in part B will receive the combination at the RP2D. Treatment will continue until confirmed radiographic disease progression according to RECIST v1.1 criteria confirmed by blinded independent central review, or unacceptable toxicity.

Six of 38 expected patients have enrolled to the first (80 mg once daily; n = 3) and second (160 mg once daily; n = 3) dose levels since accrual begin in March 2022. Recruitment is expected to be completed by March 2023.

Aguilar A, Cobo M, Azkarate A, et al. Design of a phase I trial (TOTEM) to test repotrectinib in combination with Osimertinib in advanced, metastatic EGFR mutant NSCLC. Presented at: 2022 World Conference on Lung Cancer. August 6-9, 2022; Vienna, Austria. Abstract EP08.02-011.

Articles

Investigators are evaluating the combination of repotrectinib and osimertinib for the treatment of patients with advanced or metastatic EGFR-mutant non–small cell lung cancer in the phase 1 TOTEM trial.

Repotrectinib Plus Osimertinib Under Study in EGFR-Mutant NSCLC

The combination of azacitidine and quizartinib produced preliminary responses in patients with myelodysplastic syndrome (MDS) and MDS/myeloproliferative neoplasms (MPN) whose tumors harbored 

 mutations, according to data from a phase 1/2 trial (NCT04493138).

At a median follow-up of 13.2 months (95% CI, 4.6-21.7), the combination elicited a 90% overall response rate (ORR; n = 9/10). Among the 10 patients, 60% had a complete response in the marrow (mCR). Additionally, a complete response, a mCR with hematologic improvement (HI), and a HI were observed in 1 patient each. The median number of cycles to best response was 1 (range, 1-6) and the median duration of response (DOR) was 6.3 months (range, 1.6-14.3).

“[The] combination of quizartinib and azacitidine [is] active in MDS and MDS/MPN, [and] no dose-limiting toxicities [DLTs] were [observed] in [the] phase 1 dose-escalation portion [of the trial] up to doses of 60 mg daily [on] days 1 to 28,” study authors from The University of Texas MD Anderson Cancer Center wrote in a poster shared during the 2022 EHA Congress. “[The regimen had an] acceptable toxicity profile.”

Approximately 1% of patients with newly diagnosed MDS harbor 

 mutations, although the mutations occur in up to 19% of patients at the time of failure of a hypomethylating agent (HMA). Additionally, approximately 10% of patients with MDS/MPN harbor 

mutations; these mutations occur in 13% to 15% of those with chronic myelomonocytic leukemia (CMML).

The phase 1/2 trial evaluated the doublet in adult patients aged 18 years of age or older with HMA-naïve MDS or MDS/MPN with intermediate-2/high-risk disease per International Prognostic Scoring System (IPSS) or higher than 5% blasts; or any MDS or MDS/MPN following failure on HMA treatment. All patients were required to have a 

-ITD/D835 mutation; they also needed to have an ECOG performance status of 0 to 2.

Patients were excluded from the study if they had a QTcF of more than 450 msec; a history of clinically significant ventricular fibrillation, torsades de pointes, sustained ventricular tachycardia, or long QT syndrome; a known history of second- or third-degree heart block; a complete left bundle branch or bifascicular block; or atrial fibrillation documented within 2 weeks of study entry.

Patients enrolled to the dose-escalation portion of the trial received either 30 mg (n = 3), 40 mg (n = 3), or 60 mg (n = 4) of oral quizartinib per day on days 1 through 28, in combination with 75 mg/m

 of azacitidine daily on days 1 through 5 of each 28-day cycle.

The primary end points of the dose-escalation portion of the trial were to evaluate safety and tolerability, and determine the maximum tolerated dose (MTD) of quizartinib. Secondary end points included ORR per International Working Group 2006 criteria, overall survival (OS), DOR, relapse-free survival, and leukemia-free survival.

At data cutoff, total of 10 patients were enrolled to the trial,; 9 patients were included in the dose-escalation portion of the research and 1 was included in dose-expansion portion. Half of all patients had intermediate-2 risk disease, and the other half had intermediate-1 risk disease per IPSS.

Seven patients presented with CMML, 2 had MDS, and 1 had atypical chronic myeloid leukemia. Six patients harbored 

 mutations. Eight patients had normal cytogenetics at baseline, 1 had complex cytogenetics, and 1 had monosomy 7 cytogenetics. The median absolute neutrophil count (ANC) was 10.68 x 10

 (range, 0.33-113.8), the median platelet count was 110 x 10

 (range, 34-536), the median hemoglobin level was 9.6 g/dL (range, 7-10.3), and the median bone marrow blasts was 8% (range, 2%-15%).

Additional data showed that the combination resulted in a median OS of 17.35 months (95% CI, 6.8-28.3). Platelet recovery to more than 50 x 10

/L by day 28 of therapy occurred in 67% and 56% of patients, respectively. Furthermore, ANC recovered to 1 x 10

At the time of data cutoff, 1 patient remained on study treatment. Reasons for discontinuation included moving to allogeneic stem cell transplant (n = 4), disease relapse (n = 1), disease progression (n = 2), and patient/physician preference (n = 2). Patients received a median of 6 (range, 1-11) cycles of treatment.

No DLTs were reported in the dose-escalation phase of the research. However, 2 patients required dose reductions of quizartinib during cycle 3 or later because of cytopenias. Additionally, 3 patients needed dose reductions of azacitidine due to cytopenias. No early mortality was reported at weeks 4 and 8.

The most frequent grade 1/2 adverse effects reported with the doublet included constipation (n = 6), oral mucositis (n = 3), diarrhea (n = 2), fatigue (n = 2), nausea (n = 2), arthralgia (n = 2), atrial fibrillation (n = 1), hypokalemia (n = 1), injection site reaction (n = 1), and skin infection (n = 1). The most common grade 3 AEs were thrombocytopenia (n = 3), anemia (n = 2), atrial fibrillation (n = 1), hypokalemia (n = 1), chest pain (n = 1), and febrile neutropenia (n = 1).

The dose-escalation phase of the research is ongoing to further evaluate the safety and efficacy of the combination, according to study authors. Additional research on lower dose levels of 40 mg of quizartinib per day are warranted.

Abuasab T, Jabbour E, Short N, et al. Initial results of phase I/II study of azacitidine in combination with quizartinib for patients with myelodysplastic syndrome and myelodysplastic/myeloproliferative neoplasm with 

 mutation. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P754.

The combination of azacitidine and quizartinib produced preliminary responses in patients with myelodysplastic syndrome and myelodysplastic syndrome/myeloproliferative neoplasms whose tumors harbored FLT3 or CBL mutations, according to data from a phase 1/2 trial (NCT04493138).

Azacitidine/Quizartinib Combo Showcases Early Activity in MDS, MDS/MPN With FLT3 or CBL Mutations

The novel PSMAxCD38 costimulatory bispecific antibody REGN5678 has shown encouraging efficacy in combination with cemiplimab-rwlc (Libtayo) in patients with advanced metastatic castration-resistant prostate cancer (mCRPC), according to preliminary findings from an ongoing phase 1/2 trial (NCT03972657).

The results showed that the higher dose levels evaluated in cohorts 6 through 8 were associated with improved anti-tumor activity within 6 weeks of starting the combination treatment. Safety data showed no evidence of grade 3 or greater immune-related adverse effects (irAEs) in nonresponding patients. Previous findings demonstrated an association between the occurrence of irAEs and anti-tumor activity.

In cohort 6 (n = 4), 1 patient experienced a 100% reduction in PSA and a complete response (CR) in target lesions based on RECIST v1.1 criteria, which was maintained for approximately 10 months. Ultimately, the patient discontinued therapy because of a grade 3 irAE of the skin that has resolved with treatment.

In cohort 7 (n = 8), 3 patients experienced a reduction in PSA of more 99%, 44%, and 22%, respectively. Two of these patients had a grade 3 AE of aseptic encephalitis and seizure, respectively, both of which have resolved.

In cohort 8 (n = 4), 3 patients experienced reductions in PSA of more than 99% (n = 2) and 82%. Of the 2 patients with greater than 99% PSA reductions, 1 experienced grade 3 mucositis that resolved and the other experienced grade 3 acute inflammatory demyelinating polyradiculopathy.

“In past clinical trials, metastatic castration-resistant prostate cancer has been largely unresponsive to PD-1 inhibition and immunotherapy in general, leaving patients with inadequate treatment options, a poor prognosis and an expected survival of one to two years depending on the treatment history,” Mark Stein, MD, a trial investigator and associate professor of medical oncology at Columbia University Vagelos College of Physicians and Surgeons, said in a press release.

“These initial data provide the first clinical evidence indicating that a costimulatory bispecific antibody may synergistically combine with an anti-PD-1 agent such as Libtayo to enable activity against a tumor class previously resistant to anti–PD-1 immunotherapy.”

In this first-in-human, open-label phase 1/2 trial, investigators are evaluating the agent for safety and efficacy in patients with advanced mCRPC who have experienced disease progression on multiple anti-androgen therapies. In the phase 1 dose-escalation portion, patients are started on weekly doses of the REGN5678 monotherapy for 3 weeks, which is then continued in combination with standard dose cemiplimab.

The primary end points are safety, tolerability, and pharmacokinetics. The key secondary end point is objective response rate defined as at least a 50% reduction of prostate-specific antigen (PSA) from baseline and/or tumor shrinkage.

Preliminary data from the ongoing dose-escalation portion of the trial captures 33 patients across 8 dose level cohorts. At the lowest dose levels evaluated in cohorts 1 through 5, investigators observed minimal anti-tumor activity, with only 1 of 17 patients showing a reduction in PSA of 22%.

Stein and colleagues have observed no grade 4 irAEs or grade 2 or greater cytokine release syndrome in the trial to date. There was 1 death reported but that was deemed to be unrelated to treatment.

“Through extensive preclinical research, we hypothesized that augmenting T-cell costimulation alongside PD-1 inhibition could be a key to turning immunologically ‘cold’ tumors ‘hot,’” said George D. Yancopoulos, MD, PhD, president, and chief scientific officer at Regeneron. “These preliminary data for our PSMAxCD28 costimulatory bispecific provide the first clinical evidence supporting the promise of our broader pipeline of costimulatory bispecifics in diverse solid tumors and hematological malignancies. By combining these costimulatory bispecifics with Libtayo or our CD3 bispecifics, we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers.”

Investigators plan to present additional data at an upcoming medical meeting.

Novel costimulatory bispecific antibody shows encouraging anti-tumor activity when combined with PD-1 inhibitor Libtayo (cemiplimab) in advanced metastatic castration-resistant prostate cancer (mCRPC). News release. Regeneron. August 3, 2022. Accessed August 3, 2022. 

The novel PSMAxCD38 costimulatory bispecific antibody REGN5678 has shown encouraging efficacy in combination with cemiplimab in patients with advanced metastatic castration-resistant prostate cancer, according to preliminary findings from an ongoing phase 1/2 trial (NCT03972657). 

REGN5678 Plus Cemiplimab Demonstrates Early Activity in mCRPC

The fully human BCMA-directed CAR T-cell therapy, CT103A, demonstrated deepening efficacy with an acceptable toxicity profile in patients with relapsed or refractory multiple myeloma, according to updated data from the phase 1/2 FUMANBA-1 trial (NCT05066646).

At a median follow-up of 9.0 months, the agent elicited an objective response rate (ORR) of 94.9% in the total patient population evaluable (n = 79), with a very good partial response or better rate of 89.9% and a complete response (CR)/stringent complete response (sCR) rate of 68.4%. The median time to response (TTR) was 16 days (range, 11-123).

Among the 10 patients who had extramedullary myeloma (EMM; n = 10), the ORR with the CAR T-cell therapy was 100%, with a CR or better rate of 90%. Those who previously received a CAR T-cell product (n = 12) also derived benefit from CT103A, although the ORR was not as high, at 75%, with a CR or better rate of 41.7%. In those without EMM who received prior CAR T-cell therapy (n = 61), the ORR with the agent was 98.4%, with a CR or better rate of 70.5%.

“Updated data from the phase 1/2 FUMANBA-1 study continue to show encouraging efficacy of CT103A with a favorable safety profile in relapsed/refractory multiple myeloma,” lead study author Chunrui Li, MD, PhD, of the Department of Hematology at Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, said in a presentation of the data during the 2022 EHA Congress. “CT103A led to a deepening and durable response with robust expansion and prolonged persistence.”

CT103A utilizes a lentiviral vector containing a CAR structure with a fully human single-chain variable fragment, CD8a hinger, and transmembrane, 4-1BB co-stimulatory and CD3ζ activation domains. By leveraging a proprietary in-house optimization platform, the construct of the BCMA-targeted therapy is hypothesized to be strong and durable.

The product was investigated as part of FUMANBA-1, which enrolled those with relapsed or refractory multiple myeloma who had previously received at least 3 therapies, including proteasome inhibitors and immunomodulatory drugs. Patients were required to have experienced disease progression during or within 1 year of their last line of therapy. They also needed to have an ECOG performance status of 0 or 1, and BCMA positivity.

The primary end point of the first phase of the trial was safety and tolerability, and secondary end points included efficacy, pharmacokinetics (PK), and pharmacodynamics (PD). For the second phase of the trial, the primary end point was efficacy in the form of ORR, and secondary end points included safety and tolerability, minimal residual disease (MRD), overall survival, duration of response, TTR, PK, and PD.

Previous data from the phase 1 study, which was conducted at 14 clinical sites throughout China, were shared during the 2021 ASH Annual Meeting and showed that the product was safe and highly active in this patient population.

As of January 21, 2022, a total of 79 patients had received the CAR T-cell therapy. The median age of these patients at baseline was 57 years (range, 39-70) and 45% were male. The median time since diagnosis was 41.3 months (range, 7.5-193.2).

Moreover, the median number of prior lines of therapy received was 5 (range, 3-23); all patients were double refractory and 16.5% of patients were triple refractory. Notably, 34.2% of patients had high-risk cytogenetics, and 12.7% of patients had EMM. Just under 30%, or 27.8%, of patients previously underwent autologous hematopoietic stem cell transplantation and 15.2% previously received CAR T-cell therapy.

Additional data showed that 92.4% of patients were MRD negative, and all patients who achieved a CR/sCR to treatment were MRD negative. Moreover, the median duration of MRD negativity was not yet reached.

The median progression-free survival in all cohorts except for those who previously received CAR T-cell therapy had not yet been reached. In those with prior CAR T, the median PFS was 7.5 months (95% CI, 2.9–not reached).

When looking at cytokines in the peripheral blood, investigators observed notable expansion, and long persistence. Serum BCMA (sBCMA) was also evaluated in the peripheral blood. sBCMA decreased to the lower limit of qualification (LLOQ) of 3.2 ng/mL at a median of 2 months following the CAR T-cell infusion. Moreover, the sBCMA level remained below the LLOQ at 12 months in those who continued to respond to treatment.

Antidrug antigen (ADA) was detected in 2.6% of the 79 patients at 3 months after infusion; at 6 and 12 months, these rates were 8.2% and 33.3%, respectively. Prior to infusion, ADA was detected in 1.3% of patients. At the median follow-up of 9 months, ADA was detected in 16.5% of patients post-CT103A infusion.

Regarding safety, grade 3 or higher treatment-related adverse effects (AEs) were experienced by 93.7% of patients who received CT103A, the most common of which being neutropenia (82.3%), followed by thrombocytopenia (59.5%), and lymphocytopenia (58.2%). Serious AEs occurred in 69.6% of patients, and included pneumonia (44.3%), thrombocytopenia (21.5%), and enteritis infectious (8.9%).

Any-grade cytokine release syndrome (CRS) was reported in most patients (94.9%); this effect was grade 1 in 73.4% of patients and grade 2 in 21.5% of patients. The median time to onset of CRS was 6 days, and the median duration of days was 5. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 2 patients; these cases were grade 1 and grade 2 in severity.

Previously, in February 2022, the FDA granted an orphan drug designation to CT103A for use as a potential therapeutic option in patients with relapsed or refractory multiple myeloma.

Li C, Wang D, Song Y, et al. Updated phase 1/2 data of safety and efficacy of CT103A, fully human BCMA-directed CAR-T cells, in relapsed/refractory multiple myeloma. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S187.

Wang D, Wang J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. 

. 2021;137(21):2890-2901. doi:10.1182/blood.2020008936

US FDA grants orphan drug designation to BCMA CAR-T cell therapy co-developed by IASO Bio and Innovent. News Release. IASO Biotherapeutics and Innovent Biologics, Inc. February 14, 2022. Accessed August 2, 2022. 

The fully human BCMA-directed CAR T-cell therapy, CT103A, demonstrated deepening efficacy with an acceptable toxicity profile in patients with relapsed or refractory multiple myeloma, according to updated data from the phase 1/2 FUMANBA-1 trial.

CAR T-cell Therapy CT103A Produces Durable Responses in Relapsed/Refractory Multiple Myeloma

The FDA has granted a fast track designation to OP-1250 for the treatment of patients with ER-positive, HER2- metastatic breast cancer. The oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader is indicated for patients who have progressed following at least 1 line of endocrine therapy with at least 1 line administered in combination with a CDK4/6 inhibitor.

OP-1250 is under investigation as a single agent in an ongoing phase 1/2 clinical trial (NCT04505826) and in combination with palbociclib (Ibrance) for patients with recurrent, locally advanced, or metastatic ER-positive, HER2- breast cancer in a phase 1b trial (NCT05266105).

“Receiving fast track designation from the FDA for OP-1250 is an important milestone for the development program and underscores OP-1250’s potential clinical utility to address a significant unmet medical need in women living with advanced ER+/HER2- breast cancer,” Sean P. Bohen, MD, PhD, president and chief executive officer of Olema Oncology, said in a press release. “We look forward to working closely with the FDA to optimize and expedite the development program, with the goal of making OP-1250 available to patients sooner.”

Earlier in November 2021, the company announced that findings from the dose-escalation portion of the open-label phase 1/2 study demonstrated favorable pharmacokinetics, tolerability, and efficacy.

“We successfully delivered on our objectives for the dose-escalation stage of our ongoing phase 1/2 trial of OP-1250, with the desired pharmacokinetics, favorable tolerability, and early but clear efficacy signals. We are particularly encouraged by the responses observed in patients who had received multiple prior lines of therapy and harbored 

 activating mutations, demonstrating that OP-1250 is an active drug and achieved sufficient exposure levels to block the ER-mediated cancer cell growth and proliferation signal,” Bohen said.

As of November 1, 2021, 41 patients with recurrent, locally advanced, or metastatic ER-positive, HER2-negative breast cancer were enrolled across 7 dose cohorts administered daily: 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 210 mg, and 300 mg.

The population was heavily pretreated, with 95% of patients previously receiving a CDK4/6 inhibitor and 22% having received at least 2 prior CDK4/6 inhibitors. Additionally, 68% of patients received prior fulvestrant (Faslodex) and 42% received prior chemotherapy in the advanced setting.

Patients received a median of 3 prior lines of anti-cancer therapy and 2 prior lines of endocrine therapy in the advanced setting. Investigators assessed circulating tumor DNA from 39 patients at baseline and detected 

Pharmacokinetic analyses demonstrated dose-proportional increases in OP-1250 exposures across all dose levels, high oral bioavailability, and steady-state plasma levels with little peak-to-trough variability. At doses of 60 mg and above, OP-1250 surpassed exposures within the predicted thresholds for maximal anti-tumor efficacy based on preclinical models.

Moreover, no dose-limiting toxicities occurred across dose levels and a maximum tolerated dose was not reached. Most adverse effects (AEs) were grade 1 or 2 across dose levels. The most common investigator-assessed treatment-related AEs were nausea (49%), fatigue (34%), vomiting (22%), and headache (17%).

Investigators observed no clinically significant bradycardia, ocular toxicities or diarrhea. The recommended phase 2 dose range of 60 mg to 120 mg once daily was identified for further evaluation.

Three of 24 efficacy-evaluable patients had partial responses (PRs), including 2 confirmed PR and 1 unconfirmed PR in a patient who had robust target lesion reduction of 100%. Notably, all 3 responses occurred in patients with 

mutations and who had previously received CDK4/6 and aromatase inhibitors, and fulvestrant. Four response-eligible patients had target lesion reductions of greater than 30%.

Across all doses, the objective response rate (ORR) was 8% (2/24) and the clinical benefit rate (CBR) was 29% (7/24). For the dose levels within the recommended phase 2 dose range, the ORR was 17% (2/12) and the CBR was 46% (6/13).

As of the data cut-off date, 32% of patients (13/41) remained on treatment with efficacy data continuing to mature.

Olema Oncology Receives FDA Fast Track Designation for OP-1250 for the Treatment of ER+ / HER2- Metastatic Breast Cancer. News release. Olema Pharmaceuticals, Inc. July 21, 2022. Accessed August 2, 2022. 

A dose escalation/expansion study of oral OP-1250 in subjects with advanced and/or metastatic HR+, HER2- breast cancer. ClinicalTrials.gov. Updated October 25, 2021. Accessed August 2, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04505826

A phase 1 study of oral OP-1250 in combination with palbociclib in HR+/HER2- breast cancer patients. ClinicalTrials.gov. Updated March 4, 2022. Accessed August 2, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05266105

Olema Oncology announces first clinical data on OP-1250 in advanced ER+ / HER2- breast cancer. News release. Olema Pharmaceuticals, Inc. November 30, 2021. Accessed August 2, 2022. 

The FDA has granted a fast track designation to OP-1250 for the treatment of patients with ER-positive, HER2- metastatic breast cancer who have progressed following at least 1 line of endocrine therapy with at least 1 line administered in combination with a CDK4/6 inhibitor.

FDA Grants Fast Track Designation to OP-1250 in ER+/HER2- Metastatic Breast Cancer

The FDA has lifted a clinical hold on the phase 1b CYAD-101-002 trial (KEYNOTE-B79; NCT04991948), which is evaluating the safety and clinical activity of the investigational CAR T-cell therapy CYAD-101 given concurrently with FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) and followed by pembrolizumab (Keytruda) in patients with unresectable metastatic colorectal cancer (mCRC).

The clinical hold was lifted after Celyad Oncology made changes to the eligibility criteria for the study. In March 2022, 

the FDA placed a clinical hold on the trial

 due to insufficient information to evaluate risk to study participants.

 In February 2022, Celyad Oncology voluntarily paused the trial to investigate reports of 2 deaths on the study.

“We are pleased that the FDA lifted the clinical hold on this trial. We remain confident in the potential development of not only the candidate itself, but the continued development with our proprietary TIM technology. CYAD-101 is currently our only clinical candidate co-expressing NKG2D and TIM, and we hope to continue to showcase our expertise with our non-gene edited technologies and explore additional opportunities to utilize NKG2D in allogeneic CAR T,” Charles Morris, MD, the chief medical officer of Celyad Oncology, stated in a press release.

CYAD-101 is an investigational, non-gene edited allogeneic CAR T-cell product that is engineered to co-express the CAR based on NKG2D, which is expressed on natural killer cells that binds to NKG2DL that are expressed by a wide range of tumor cells and the inhibitory peptide TIM.

 TIM expression reduces signaling of the TCR complex by interfering with the CD3ζ component of the complex.

KEYNOTE-B79 is enrolling patients with histologically proven metastatic unresectable adenocarcinoma of the colon or rectum who have a confirmed non-microsatellite instability high/mismatch-repair proficient tumor status, unequivocal and measurable disease per RECIST v1.1 criteria, recurrent or progressive disease after at least 1 line of systemic therapy for metastatic disease that must include FOLFOX, are due to receive FOLFOX, and have neurotoxicity of no more than Common Terminology Criteria for Adverse Events grade 1 from prior chemotherapy.

Additional inclusion criteria include an ECOG performance status of 0 or 1; adequate organ, hepatic, renal, pulmonary, and cardiac function; and tumor biopsy at screening.

Patients will be excluded from the trial if they receive any other investigational agent or device within 4 weeks of first study treatment; receive any anticancer agent within 4 weeks of first study treatment; are administered filgrastim or similar growth factors within 7 days of first study treatment; have prior treatment with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent; receive radiotherapy within 2 weeks of first study treatment; or have major surgery within 4 weeks before the start of study treatment.

Primary end points of the trial include occurrence of dose-limiting toxicities and objective response rate.

Celyad Oncology announces FDA lifts clinical hold of CYAD-101-002 phase 1b trial. News release. Celyad Oncology SA. August 1, 2022. Accessed August 1, 2022. 

Celyad Oncology announces clinical hold of CYAD-101-002 phase 1b trial. News release. Celyad Oncology SA. March 2, 2022. Accessed August 1, 2022. 

Celyad Oncology SA. Pipeline. Accessed August 1, 2022. 

Study of pembrolizumab treatment after CYAD-101 with FOLFOX preconditioning in metastatic colorectal cancer. ClinicalTrials.gov. Updated March 9, 2022. Accessed August 1, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04991948

The FDA has lifted a clinical hold on the phase 1b KEYNOTE-B79 trial, which is evaluating the safety and clinical activity of CYAD-101 given concurrently with FOLFOX and followed by pembrolizumab in patients with unresectable metastatic colorectal cancer.

Pipeline Report: August 2022 | Articles

Repotrectinib Plus Osimertinib Under Study in EGFR-Mutant NSCLC

Azacitidine/Quizartinib Combo Showcases Early Activity in MDS, MDS/MPN With FLT3 or CBL Mutations

REGN5678 Plus Cemiplimab Demonstrates Early Activity in mCRPC

CAR T-cell Therapy CT103A Produces Durable Responses in Relapsed/Refractory Multiple Myeloma

FDA Grants Fast Track Designation to OP-1250 in ER+/HER2- Metastatic Breast Cancer

FDA Lifts Clinical Hold on KEYNOTE-B79 Trial Evaluating CAR T-cell Therapy CYAD-101 in Metastatic CRC