Reading our newsletter will keep you up to date with last month’s news items on oncology drug development!

NEWS AND PUBLICATIONS

Promise and Potential of the Next-Generation Immune Checkpoint LAG-3 for Oncology Patients

Lymphocyte-activation gene 3 (LAG-3, CD223), a type1 transmembrane protein, LAG-3 was identified in 1990 by Triebel et al. LAG-3 is expressed on exhausted CD4+ and CD8+ tumor-infiltrating T cells that are defective in cytokine production. LAG-3 is also expressed on Treg cells in the peripheral blood and in tumor tissues of patients with different cancer types. It has been shown that LAG-3-expressing Treg cells produce high levels of immunoregulatory cytokines IL-10 and TGF-β and suppress tumor-specific T cells. Additionally, the level of LAG-3 expression and infiltration of LAG-3+ cells into tumors have been associated with tumor progression, poor prognosis, and unfavorable clinical outcomes in various tumors, such as colorectal cancer, renal cell carcinoma, follicular lymphoma, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer, breast cancer, and diffuse large B cell lymphoma. These results strongly indicate that LAG-3 contributes to immune escape mechanisms in tumors similar to PD-1. LAG-3 blockade has been demonstrated to re-activate exhausted T cells and strengthen anti-tumor immunity in non-clinical studies and turn ‘cold tumors into hot tumors’.

cancer-photo
Image from the Dana-Farber Cancer Institute. Image Source.

The translation of these findings into the clinic with promising initial results was just announced by Bristol-Myers Squibb (for relatlimab) and Merck & Co (for favezelimab) at ASCO.

Results of the phase 2/3 RELATIVITY-047 trial in patients with metastatic or unresectable melanoma, showed significantly longer PFS in patients receiving the combination of relatlimab plus nivolumab (anti-PD-1) vs nivolumab alone, 10.12 months vs 4.63 months, respectively. Interestingly, the PFS benefit of the fixed-dose combination was observed early, at the time of the first scan, and was consistent over time.

Merck & Co presented data from a phase 1 study in a small group of metastatic colorectal cancer patients showing a combination of favezelimab with pembrolizumab (anti-PD-1) could have potential in metastatic colorectal cancer (NCT02720068). Data from 80 patients whose cancer progressed after two treatment lines, showed responses in 6.3%, with one complete response. The median PFS was 2.1 months and median OS of 8.3 months was observed. To note, the combination performed better in a group of 36 patients whose tumors expressed high levels of PD-L1. Responses were reported in 11.1% of patients with a median OS of 12.7 months. After one year of treatment, 51% of these patients were still alive, compared with 40.8% in the overall combo group. As Merck noted, ‘the 11.1% may seem low, but it’s an improvement on the 0% Merck would expect in this population’.

Currently, around 20 companies are researching LAG-3 targeting drugs.

INDUSTRY

  • Agenus and Bristol Myers Squibb have announced an exclusive global license for Agenus’ anti-TIGIT bispecific antibody program with a phase 1 to start in 2021. The bispecific antibody program, AGEN1777, blocks TIGIT and a second undisclosed target and is an Fc-enhanced antibody in late preclinical development designed to target major inhibitory receptors expressed on T and NK cells to improve anti-tumor activity. In preclinical studies this approach has shown significant potential in tumor models where anti-PD-1 or anti-TIGIT monospecific antibodies alone are ineffective.

EMA

In May, the Committee for Medical Products for Human Use (CHMP) adopted a positive opinion for:

Extensions of indications:

  • Blincyto (AMGEN Europe BV), a bispecific CD19-directed CD3 T-cell engager, as monotherapy for the treatment of pediatric patients aged 1 year or older with high-risk first relapsed Philadelphia chromosome negative CD19 positive B-precursor ALL as part of the consolidation therapy
  • Darzalex (Janssen-Cilag International N.V.), an anti-CD38 monoclonal antibody, for multiple myeloma in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one prior therapy containing a proteasome inhibitor and lenalidomide and were lenalidomide-refractory, or who have received at least two prior therapies that included lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or after the last therapy; and for the treatment of adult patients with newly diagnosed systemic light chain (AL) amyloidosis, Darzalex is indicated in combination with cyclophosphamide, bortezomib and dexamethasone.
  • Keytruda (Merck Sharp & Dohme B.V.), an anti-PD-1 antibody, in combination with platinum and fluoropyrimidine based chemotherapy, indicated for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumors express PD‑L1 with a CPS ≥ 10
  • Libtayo (Regeneron), an anti-PD-1 antibody, is indicated for the treatment of adult patients with locally advanced or metastatic basal cell carcinoma (laBCC or mBCC) who have progressed on or are intolerant to a hedgehog pathway inhibitor (HHI) and is indicated for the first-line treatment of adult patients with non-small cell lung cancer (NSCLC) expressing PD-L1 (in ≥ 50% tumor cells), with no EGFR, ALK or ROS1 aberrations, who have locally advanced NSCLC (who are not candidates for definitive chemoradiation) or metastatic NSCLC

New Indication:

  • Opdivo, an anti-PD-1 antibody, in combination with Yervoy, an anti-CTLA-4 antibody (both Bristol-Myers Squibb), are indicated for the treatment of adult patients with mismatch repair deficient or microsatellite instability high metastatic colorectal cancer after prior fluoropyrimidine based combination chemotherapy

FDA

In May, the FDA granted accelerated approval for:

  • Pembrolizumab (Keytruda, Merck & Co.) in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, based on results from the KEYNOTE-811 (NCT03615326) trial.
  • Amivantamab-vmjw (Rybrevant, Janssen Biotech, Inc.) for adult patients with locally advanced or metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations that progressed on or after platinum-based chemotherapy, based on the CHRYSALIS clinical trial (NCT02609776). 
  • Sotorasib (Lumakras™, Amgen, Inc.), a RAS GTPase family inhibitor, for adult patients with KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA  approved test, who have received at least one prior systemic therapy based on results of the CodeBreaK 100 clinical trial (NCT03600883).
  • Infigratinib (Truseltiq, QED Therapeutics, Inc.), a kinase inhibitor for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test based on efficacy results of the CBGJ398X2204 trial (NCT02150967).
  • Nivolumab (Opdivo, BMS) or patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy. Efficacy was evaluated in CHECKMATE-577 (NCT02743494), a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or GEJ cancers who had residual pathologic disease following concurrent chemoradiotherapy. 

FDA guidance documents of interest:

Bispecific Antibody Development Programs Guidance for Industry (Final May2021)

This guidance provides recommendations to assist industry and other stakeholders involved in the development of bispecific antibodies. In addition to general considerations, the guidance provides recommendations for specific regulatory, quality, nonclinical, and clinical considerations for bispecific antibody development programs. Although this guidance is intended for bispecific antibodies, the principles discussed in this guidance may also inform the development of other types of bispecific protein products and multi-specific products.

E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (Final May2021)

To properly inform decision-making by pharmaceutical companies, regulators, patients, physicians, and other stakeholders, clear descriptions of the benefits and risks of a treatment (medicine) for a given medical condition should be made available. Without such clarity, there is a concern that the reported treatment effect will be misunderstood. This addendum presents a structured framework to strengthen the dialogue between disciplines involved in the formulation of clinical trial objectives, design, conduct, analysis and interpretation, as well as between sponsor and regulator regarding the treatment effect or effects of interest that a clinical trial should address.

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