Targeted cancer therapy continues to evolve, and many new treatment combinations are being approved in addition to developmental advancements in novel checkpoint inhibitors. This article will address the lately approved antibody therapeutics (US and EU), those in regulatory review, the expanded approval of existing immunotherapies, and their associated companion diagnostics for cancer treatment. This article will address the following issues:
Antibody-Based Biopharmaceuticals Approved Between 2021-2022
Between 2021 to 2022, the FDA approved six new antibody-based immunotherapies and EMA five whereas four of the five accepted were previously cleared by the FDA, Table 12,3.
Table 1: Antibody therapeutics approved in the EU or US
Starring 2021’s approval is Dostarlimab (Jemperli), anti-PD-1 Humanized IgG4, and Amivantamab (Rybrevant), a bispecific antibody targeting cancer epitopes, EGFR and MET. Both were approved in the EU (M.A. No. EU/1/21/1538/001) and US (BLA:761174/761210) to treat tumors with a high mutational burden and NSCLC with EGFR exon 20 mutations, respectively.
Companion Diagnostics and Future Artificial Intelligence (AI)-Based Approaches
The use of immune signature to predict immunotherapeutic response led to an increase in the development and approval of immunohistochemical (IHC) diagnostic assays, Table 24. Such devices allow informative decision-making to assess tumor-favoring immune responsiveness5,6. For example, the VENTANA MMR RxDx panel was approved concomitantly with Dostarlimab (mentioned above) to distinguish the patients with dMMR who will benefit from this treatment7. Additional FDA-approved companion diagnostic tests are listed below, Table 2.
Table 2: List of Approved Companion Diagnostic Devices
In that regard, most IHC stained slides are visualized directly under a conventional light microscope or scanned and converted to digital slides that allow remote examination by a qualified pathologist. But alongside the manual assessment, Artificial Intelligence and Machine Learning (AI/ML) -based software solutions as a Medical Device (SaMD) are being developed as promising approaches for fast, quantitative, and accurate pathologic assessment8,9. Thus, the demand for a clear regulatory framework to develop AI/ML-based SaMD has grown, and in 2021, the FDA released an action plan for a potential approach to premarket review (with a feedback request)10. In addition, 10 guiding principles that inform the development of Good Machine Learning Practice (GMLP) were written cooperatively with the Health Canada and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA)11. Although this developed technology is partially adopted in research use only (RUO) settings12, and its use in the clinic is mainly for observational studies8,9, AI will likely alter immunotherapy practice in the near future.
Expanded Indication Approvals
Important past year’s (2021) step in the immunotherapeutic approach is the expanded indication approvals for several already in-use drugs as adjuvant/neo-adjuvants therapies for the core axis PD-1/PD-L1. PD-1/PD-L1 blockade was proven to promote DFS (Disease-Free Survival) and EFS (Event-Free Survival). Atezolizumab (Tecentriq) had been cleared by the FDA as an adjuvant treatment with the companion diagnostic test VENTANA PD-L1 (SP263), mentioned above, for NSCLC (non-small-cell lung cancer) patients expressing PD-L113. Pembrolizumab (Kytruda) was approved both by EMA and FDA for the adjuvant treatment of RCC (Renal Cell Carcinoma) and neoadjuvant+adjuvant treatment for TNBC (Triple Negative Breast Cancer), respectively 14,15 . Nivolumab(Opdivo) has also been approved by the E.C. (European Commission) and the FDA for the adjuvant treatment of esophageal or GEJ (gastroesophageal junction) cancer16,17. The latter had also approved Nivolumab for adjuvant therapy of urothelial carcinoma18.
Latest Advancements in the Immunotherapy Field and 2022 Expected Approvals
The Immune Checkpoint Inhibitors (ICIs) to CTLA-4 and PD1/PDL1 is still at the top of the drug development pyramid. However, there have been recent advancements in understanding the mechanisms tumor cells exploit to evade the immune system19,20. Therefore, high hopes are pinned on additional immune and cancer-specific targets. The next wave of immunotherapies includes two promising immune inhibitory checkpoints, TIGIT (NCT03563716, NCT04570839, NCT04354246) and LAG3 (NCT03470922). The FDA recently approved LAG-3 inhibitory antibody as a first in class-fixed dose combination with PD-1 inhibitor (nivolumab), Table 1. This combination therapy established more than doubled median progression-free survival compared to the nivolumab arm. These results reinforce the growing perception that targeting two different immune checkpoints and other various types of combination therapy can be more beneficial than monotherapy. Additional expected submissions or approvals include CD137 (NCT01307267), OX40 (NCT02737475), CD20, BCMA, gp100 and EpCAM21,Table 3 2,3.
Table 3: 2022 expected approvals in EU or the US
Regulatory Perspective on mAbs Marketing Approval
From a regulatory point of view, the unexpected immune response of antibody-based biopharmaceuticals is one of the obstacles when developing biological products. Thus it is advised to navigate the strategic and regulatory decisions correctly to properly assess the safety and efficacy of such biotherapeutic 22. These assessments are usually conducted during pivotal clinical trials; as per ICH S6(R1), nonclinical immunogenicity data are not considered to be predictive of clinical safety 23. Even a greater challenge arises when designing antibody-based immunotherapy with expansion to dual targets i,e. Bispecific Antibodies (bsAbs). Such a strategy may increase immunogenicity issues which may also be related to novel complex structures. Consequently, for benefit-risk assessment, the FDA may request a comparison of the bsAb to an approved monospecific product directed against the same antigenic target(s)24.
In any circumstance, every applied BLA needs to show a clinical advantage. For example, FDA denied the approval of Retifanlimab (PD1-targeted mAb)25and Oportuzumab monatoxalso (EpCAM-targeted immunotoxin, ADC), questioning their clinical benefit. In addition, concerns were raised about the Oportuzumab monatoxalso company’s CMC (Chemistry, Manufacturing, and Controls) processes26.
Accelerated approvals are granted to many I.O. biologics; however, some are not reviewed for years. In 2021, FDA conducted an industry-wide evaluation of such drug approvals, which failed to meet post-marketing requirements 27,28. Following FDA’s call into question, several immunotherapy indications were withdrawn and removed from the US market28,29,30.
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This article was prepared by:
Vered Ben Hur. Ph.D
Pharma Regulation Projects Manager
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