Bispecific antibodies: success story continues

A great number of clinical studies confirmed high efficacy and safety of bispecific antibodies in the treatment of various cancers. Breaking results from another three, evaluating amivantamab, blinatumomab and tarlatamab, continue their success story.
In these recently completed studies, amivantamab extended the progression-free survival in non-small cell lung cancer (NSCLC) from 6.7 to 11.4 months, blinatumomab increased overall survival of infants with lymphoblastic leukemia from 65.8% to 93.3%, while tarlatamab produced 32%-40% overall response rate in previously treated small-cell cancer.
Bispecifics are a dynamically developing group of biologics, which marks another milestone in the evolution of cancer therapy. Several molecules, including amivantamab and blinatumomab, have already been included in the treatment guidelines. Now that the strategy of targeting more than one antigen has been validated in clinical settings, pharmaceutical companies are pursuing the development of trispecific antibodies.

Bispecific antibodies work by simultaneously binding two distinct antigens or epitopes, enabling the precise targeting of immune system to malignant cells (in a process called immunotargeting). This strategy was hoped to produce a more potent anti-tumor response than with monospecific antibodies. The astounding results of the recently completed large-scale trials show that bispecifics have fully met these expectations. One by one, studies are reporting extraordinarily high responses, even among the previously-treated patients burdened with treatment-resistant cancers. Among the multiple clinical studies with bispecifics concluded in 2023, three Phase II/III trials of amivantamab, blinatumomab and tarlatamab stand out as providing most solid evidence of their effectiveness.

Amivantamab, a bispecific targeting EGFR and MET proteins, administered on the top of standard chemotherapy, was shown to delay the progression in patients suffering from non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions. Median survival without progression was 6.7 months in chemotherapy alone group and 11.4 months in chemotherapy plus amivantamab group. There was also a trend towards the improved overall survival. Adverse effects included reversible hematologic and dermatologic toxicities.

The second drug, blinatumomab, has been found to extend the disease-free survival and overall survival in infant lymphoblastic leukemia. This bispecific antibody binds CD19 antigen expressed on leukemic cells and CD3 antigen residing on the surface of T cells. This binding directs the T-cells to leukemic cells, causing their destruction – for this reason drugs such as blinatumomab are referred to as T-cell engagers. Blinatumomab added to standard chemotherapy nearly doubled the 2-year disease-free survival as compared with historical controls (81.6% versus 49.4%). The corresponding values for overall survival were 93.3% and 65.8%, meaning that almost 30% more patients were alive at 2 years than expected. Infant lymphoblastic leukemia is a rare disease and only 30 patients could be included in the trial, making it necessary to employ historical controls instead of a concurrent control group. The disease is associated with poor survival, even when chemotherapy is initiated soon after diagnosis, which makes the trial results even more astonishing.

Finally, another T-cell engager called tarlatamab, claimed success in a Phase II clinical trial with previously treated small-cell lung cancer patients. A group of two hundred and twenty patients, who mostly received two previous therapies, were treated with either 10 mg or 100 mg of this antibody. Objective response were registered in 40% and 32% patients in 10 mg and 100 mg groups, respectively. The corresponding median times to progression were 4.9 and 3.9 months. Although the study did not include a placebo or no treatment group, the relatively high response rates and promising survival data strongly indicated the significant anti-tumor activity of the investigated bispecific. The drug also appeared to be safe as only 3% of patients had to discontinue it because of intolerable adverse reactions.

Just like antibody-drug conjugates, bispecific antibodies are a dynamically developing group of biologics, which is expected to further boost the survival of cancer patients on the top of other innovative medicines discovered in the recent decades. The introduction of monoclonal antibodies in 1980’s and 1990’s was a major step forward in cancer treatment and now after 30 years bispecifics (together with ADCs and advanced therapies) are ready to take another. Currently, more than 110 candidates from this group are being tested in clinical trials, and many more are in pre-clinical development.

The treatment guidelines are still evolving but some bispecifics have already been incorporated as a standard of care. This is the case for blinatumomab, first bispecific approved by the FDA, recommended in recurrent acute lymphoblastic leukemia and amivantamab, which is a new treatment option for EGFR-mutated NSCLC. While bispecific antibodies are spreading their wings, trispecific ones are already appearing on the horizon. Trispecific antibodies are expected to tackle both the complex biology of cancer and emergence of treatment resistance. Several molecules have been already developed, which mostly act as T-cell engagers with additional binding to immunomodulating receptors expressed on malignant cells. We already know that two targets can be better than one, but can three be better than two? Future studies will tell.

Prepared by:

Adam Tuszyner

References

Zhou, Caicun, et al. “Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions.” New England Journal of Medicine 389.22 (2023): 2039-2051.
van der Sluis, Inge M., et al. “Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.” New England Journal of Medicine 388.17 (2023): 1572-1581.
Ahn, Myung-Ju, et al. “Tarlatamab for patients with previously treated small-cell lung cancer.” New England Journal of Medicine 389.22 (2023): 2063-2075.
Sun, Yanze, et al. “Bispecific antibodies in cancer therapy: target selection and regulatory requirements.” Acta Pharmaceutica Sinica B (2023).
Tapia-Galisteo, Antonio, et al. “When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy.” Theranostics 13.3 (2023): 1028.
NCCN Guidelines for Acute Lymphoblastic Leukemia V.1.2022 (November 19, 2022).
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