FDA Grants Orphan Drug Designation to CYNK-101 for HER2+ Gastric/GEJ Cancers

The FDA has granted an orphan drug designation to the off-the-shelf natural killer (NK) cell therapy CYNK-101 as a potential treatment for patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to Celularity, the developer of the allogeneic cell therapy.¹

CYNK-101 is currently being investigated in combination with standard frontline chemotherapy, trastuzumab (Herceptin), and pembrolizumab (Keytruda) for patients with HER2-positive gastric and GEJ cancer in a phase 1/2a study (NCT05207722). In mid-January, the FDA granted CYNK-101 a fast track designation for this combination,² which was preceded in November 2021 by the approval of an investigational new drug application for the agent, marking a rapid development timeline.

“This designation underscores the significant unmet need for these patients and CYNK-101’s potential in a new first-line treatment strategy,” Robert Hariri, MD, PhD, founder, chairman, and chief executive officer of Celularity, said in a statement. “We are grateful for the FDA’s recognition of this potential treatment paradigm through orphan drug designation and fast track designation, which we received earlier this year. At Celularity, we are committed to forging new treatment strategies that leverage the unique properties of placental-derived cellular therapies to improve the lives of patients with this difficult-to-treat cancer.”

CYNK-101 is manufactured from human placental hematopoietic stem cells, which are genetically modified to express a high-affinity and cleavage-resistant CD16 variant (FCGRIIIA). In addition to innate NK cell functions, the therapy is meant to support antibody-dependent cellular cytotoxicity (ADCC) when used in combination with other tumor-targeted monoclonal antibodies, in this case HER2-targeted trastuzumab.

“The addition of cleavage-resistant CD16 significantly augments the antibody-dependent activity of our natural killer cell therapy. To date, we have seen promising clinical data from our unmodified NK cellular therapies and believe this genetically modified construct has significant potential in a range of indications," Andrew Pecora, MD, president of Celularity, said in a statement. "In our Phase 1/2a clinical trial of CYNK-101, we are excited to explore a multipronged strategy of our NK cells and activated T cells through check point inhibition to potentially enhance overall outcomes achieved with traditional chemotherapy and trastuzumab in HER2/neu positive G/GEJ adenocarcinoma.”

The initial phase of the study will assess 2 escalating doses of CYNK-101 in combination with recombinant human Interleukin-2 (rhIL-2). Prior to infusion of the cell therapy, patients will receive induction therapy with a fluoropyrimidine or platinum-based chemotherapy regimen in combination with pembrolizumab at 200 mg on day 1 of each 3-week cycle and trastuzumab at an 8 mg/kg loading dose and then 6 mg/kg maintenance dose administered on day 1 of each 3-week cycle. Fludarabine, cyclophosphamide, and mesna will be administered as part of a 3-day lymphodepletion regimen prior to infusion of the cell therapy.

The phase 1/2a study is enrolling participants in an open 3+3 open label study design. The target enrollment will be 52 participants with HER2-positivie gastric or GEJ adenocarcinoma. Phase 2 of the study will explore the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) from phase 1 with the same lymphodepletion and induction regimens.The phase 1 primary end points are DLT and MTD, with secondary end points assessing response rates. The phase 2 primary outcome measure is overall response rate by RECIST 1.1 investigator criteria. Secondary end points will focus on progression-free survival, duration of response, overall survival, and adverse events across both phases of the study.

Those who have received prior systemic therapy for locally advanced unresectable or metastatic disease will be excluded from the study, as will those who received radiotherapy within 14 days or surgery, open biopsy, or significant traumatic injury within 28 days prior to visit 2 in the study. Prior to entry in the study, all patients are required to undergo a biopsy to confirm HER2 status.

The addition of the cell therapy adds to a recently approved triplet for patients with gastric/GEJ cancer. In May 2021, the FDA granted accelerated approval to the frontline combination of pembrolizumab, trastuzumab, and fluoropyrimidine- and platinum-containing chemotherapy for patients with HER2-positive gastric or GEJ adenocarcinoma.³ The approval was based on findings from the KEYNOTE-811 study, which was presented at the 2021 ASCO Annual Meeting shortly following the approval.⁴

In the phase 3 study, overall response rate (ORR) was 74.4% (95% CI, 66.2%-81.6%) with the addition of pembrolizumab to standard therapy of chemotherapy and trastuzumab. This was compared with 51.9% (95% CI, 43%-60.7%) for standard therapy and placebo (P = .00006). The complete response rates were 11.3% with pembrolizumab vs 3.1% with placebo. The median duration of response was 10.6 months with the addition of pembrolizumab compared with 9.5 months in the placebo group.

In addition to genetically modified NK-cell therapy, Celularity has also received 2 fast track designations for CYNK-001, which is an unmodified NK-cell therapy. These designations were for the development of the therapy for acute myeloid leukemia and recurrent glioblastoma multiforme.

References

1. Celularity receives orphan drug designation from U.S. FDA for its NK cell therapy CYNK-101 in development for the first-line treatment of advanced HER2/neu positive gastric and gastroesophageal junction cancers. News release. Celularity. January 18, 2022. Accessed February 15, 2022. https://bit.ly/3GWIpBw
2. Celularity receives fast track designation from U.S. FDA for its NK cell therapy CYNK-101 in development for the first-line treatment of advanced HER2/neu positive gastric and gastroesophageal junction cancers. News release. Celularity. January 18, 2022. Accessed February 15, 2022. https://bit.ly/3tyy3Vv
3. Janjigian YY, Kawazoe A, Yanez PE, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initial findings of the global phase 3 KEYNOTE-811 study. J Clin Oncol. 2021;39(suppl 15):4013. doi:10.1200/JCO.2021.39.15_suppl.4013
4. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed February 15, 2022. https://bit.ly/3yp08Ow.