The AACR Annual Assembly 2023, held April 14-19, commemorated a number of milestones, together with the twenty fifth anniversary of the approval of the blockbuster breast most cancers drug trastuzumab (Herceptin).
Coincidentally, Lisa Coussens, PhD, MD (hc), FAACR, FAIO, who closed out her time period as AACR President in the course of the assembly, performed a major position within the story of trastuzumab. In 1985, as a postdoctoral fellow within the lab of Axel Ullrich, PhD, FAACR, Coussens and colleagues cloned the gene HER2, which encoded a cell floor receptor that would drive cell progress and proliferation. A number of years later, researchers found that overexpression of HER2 drove the expansion of breast tumors.
One resolution was to stymie the development of cancers that specific the HER2 receptor with the antibody trastuzumab, which blocks the operate of HER2.
“The impression of trastuzumab has been big. It modified drug discovery in pharma and biotech,” mentioned, H. Michael Shepard, PhD, president, Chief Govt Officer, and Chief Scientific Officer of Enosi Therapeutics, in the course of the Annual Assembly session honoring the anniversary of trastuzumab’s approval. “This program created the present paradigm for biomarker-driven drug discovery and improvement.”
In 2019, Shepard, Ullrich, and Dennis Slamon, MD, PhD, FAACR, gained the Lasker-DeBakey Scientific Medical Analysis Award for the event of trastuzumab—a prestigious achievement, however removed from the one recognition the drug has acquired. The Galien Basis named trastuzumab Greatest Biotech Product of the 12 months in 2000 and Greatest Biotech Product of the Final 50 Years in 2022.
Though trastuzumab remodeled the panorama of breast most cancers remedy on the time of its approval, Shepard emphasised that, “Trastuzumab was a very good first step, not the entire thing.” He defined that its full impression could be largely formed by the remedies it impressed.
The Journey to Approval
Slamon, director of Scientific/Translational Analysis and the Revlon/UCLA Girls’s Most cancers Analysis Program on the College of California Los Angeles Jonsson Complete Most cancers Middle, set the stage by describing the panorama of most cancers analysis within the mid- to late-Eighties, when HER2 was first found.
“Most cancers was recognized, characterised, and categorized by the organ by which it occurred,” Slamon mentioned, explaining that every tumor kind was “handled with … a one-size-fits-all method.”
The ideas of focused remedy and most cancers subtyping have been solely starting to emerge. Subsequently, Slamon and colleagues’ 1987 findings that the HER2 gene was amplified or rearranged in round 30% of breast cancers and that these modifications correlated with a poorer prognosis have been putting. In a follow-up paper, the researchers confirmed that HER2 overexpression may drive tumor progress in preclinical fashions.
So how may researchers block it?
The reply got here serendipitously, defined Gail Lewis, PhD, a senior principal scientist of know-how and translational oncology at Genentech. Lewis and colleagues designed a HER2-targeted antibody to display that blocking HER2 boosts the efficacy of one other breast most cancers remedy underneath improvement. As an alternative, they discovered that the antibody was fairly efficient by itself.
The staff pivoted towards creating a therapeutic antibody, though the percentages on the time weren’t of their favor. “Folks had tried antibodies for years, and so they hadn’t labored, particularly in stable tumor indications,” Lewis mentioned. “There was numerous skepticism about that.”
To make use of their mouse-derived antibodies within the clinic, the researchers needed to humanize them, changing a number of of the antibody’s mouse items with human items so the affected person’s immune system wouldn’t reject the remedy. Methods to supply humanized antibodies at a therapeutic scale weren’t but developed.
However, the candidate antibody 4D5, which might be developed into trastuzumab, was efficiently humanized and entered section I medical trials by 1992.
After years of medical testing, trastuzumab turned the primary totally humanized antibody to be authorised by the U.S. Meals and Drug Administration (FDA) in 1998. Within the section III trial on which the approval was based mostly, sufferers with treatment-naïve, HER2-overexpressing breast tumors handled with chemotherapy plus trastuzumab had an extended time to illness development, an extended length of response, and a 20% decrease danger of demise than these handled with chemotherapy alone.
In 2006, trastuzumab plus chemotherapy was authorised to deal with sufferers after their HER2-overexpressing breast tumors have been surgically eliminated. Round this time, researchers additionally found that HER2 is usually overexpressed in different most cancers varieties, together with gastric most cancers. In 2010, trastuzumab plus chemotherapy was authorised to deal with HER2-overexpressing cancers of the abdomen and the gastroesophageal junction.
An Inspiration for Different HER2-targeted Therapies
The medical success of trastuzumab spurred researchers to discover related therapies concentrating on HER2.
Small molecule inhibitors. In 2001, the FDA authorised the primary tyrosine kinase inhibitor (TKI), opening the door for the event of medication concentrating on different tyrosine kinases, similar to HER2.
The identical 12 months, researchers developed lapatinib (Tykerb), a small molecule inhibitor of HER2 and its shut cousin, the epidermal progress issue receptor (EGFR). Lapatinib earned FDA approval in 2007, together with the chemotherapy capecitabine (Xeloda), for sufferers with metastatic HER2-positive breast most cancers who didn’t reply to or relapsed following remedy with trastuzumab. The mixture acquired accelerated approval to be used within the first-line setting in 2010.
Scientists developed new generations of HER2-targeted TKIs to beat resistance, improve specificity, and deal with sufferers who didn’t reply to different HER2-targeting therapies. Neratinib (Nerlynx) together with capecitabine was authorised to deal with early-stage breast most cancers in 2017 and metastatic breast most cancers in 2020. Tucatinib (Tukysa), the one presently authorised HER2 inhibitor that solely inhibits HER2, was authorised, together with trastuzumab and capecitabine, to deal with superior or metastatic breast most cancers in 2020. Tucatinib plus trastuzumab acquired an accelerated approval to deal with HER2-positive colorectal most cancers in 2023.
Different antibodies. The success of trastuzumab additionally drove researchers to re-examine different HER2-targeted antibodies developed alongside trastuzumab. One would later change into often known as pertuzumab (Perjeta), and researchers discovered it had a distinct mechanism of motion than trastuzumab.
To activate downstream signaling, one HER2 molecule should companion with one other, or with a molecule of the associated receptor HER3. Whereas trastuzumab prevented HER2 molecules from forming dimers with one another, pertuzumab prevented HER2 from dimerizing with HER3. Subsequently, researchers hypothesized that combining each antibodies might enhance HER2 inhibition by blocking each of its signaling shops.
In a section III medical trial, sufferers with HER2-positive metastatic breast most cancers had a median progression-free survival of 18.5 months when handled with pertuzumab, trastuzumab, and docetaxel, as in contrast with 12.4 months when handled with trastuzumab and docetaxel alone.
These information led to the 2012 FDA approval of trastuzumab, pertuzumab, and docetaxel for sufferers with HER2-overexpressing metastatic breast most cancers. In 2013, the mix was granted an accelerated approval to be used earlier in a affected person’s remedy plan, previous to surgical procedure. The accelerated approval was transformed to a full approval in 2017, on the similar time that the mix was authorised to deal with sure early-stage breast cancers after surgical procedure as nicely.
Antibody-drug conjugates. A brand new know-how that emerged within the early 2000s linked cancer-targeting antibodies to poisonous payloads for extremely focused tumor cell killing. Researchers sought to develop such an antibody-drug conjugate (ADC) to focus on HER2.
In 2008, they developed trastuzumab emtansine (Kadcyla, T-DM1), an ADC consisting of a trastuzumab antibody certain to the drug emtansine, which disrupts the microtubules that type a part of a cell’s inside skeleton. In a section III medical trial, sufferers with metastatic breast most cancers that was beforehand handled with at the least one HER2-targeting remedy had a forty five% decrease danger of illness development or demise when handled with T-DM1, as in contrast with sufferers handled with lapatinib plus chemotherapy. These information led to the 2013 approval of T-DM1 for this indication.
Whereas T-DM1 underwent medical improvement, researchers sought alternatives to enhance upon its design, and so they produced one other ADC referred to as trastuzumab deruxtecan (Enhertu, T-DXd). Deruxtecan, the poisonous payload of T-DXd, blocks an enzyme essential for DNA replication.
Deruxtecan can even diffuse by means of the cell membrane, which means it may well cross out of focused cells and kill close by tumor cells with variable HER2 expression. Additional, T-DXd packs a mean of eight drug molecules onto every trastuzumab spine, in comparison with T-DM1’s common of 4.
In 2019, researchers demonstrated that T-DXd was efficient in sufferers beforehand handled with T-DM1, which led to the accelerated approval of T-DXd for sufferers with metastatic breast most cancers who had acquired two prior strains of HER2-targeted remedy. The total approval got here in 2022 following a head-to-head comparability of T-DXd to T-DM1, which confirmed vital advantages in total survival, progression-free survival, and total response charge in sufferers receiving T-DXd.
In the meantime, researchers observed that, in contrast to different HER2-targeted therapies, T-DXd was efficient in preclinical fashions with low or regular expression of HER2. In medical research, sufferers with beforehand handled HER2-low tumors skilled a median progression-free survival of 9.9 months and an total survival of 23.4 months when handled with T-DXd, in contrast with 5.1 months and 16.8 months, respectively, when handled with chemotherapy. These information resulted within the approval of T-DXd in 2022 for sufferers with unresectable or metastatic HER2-low tumors after at the least one prior line of chemotherapy.
The Way forward for HER2 Focusing on
The presenters additionally provided concepts about HER2-targeting therapies which will emerge sooner or later.
Lewis mentioned bispecific antibodies—molecules that comprise two antibody fragments concentrating on totally different proteins or totally different websites on the identical protein. In some instances, the aim of bispecific antibodies could be to double down on inhibition; a bispecific antibody comprised of trastuzumab and pertuzumab, for instance, may improve the HER2 blockade. Equally, a bispecific antibody concentrating on each HER2 and HER3 may intervene with each signaling pathways to optimally block tumor progress.
Bispecific antibodies can even carry most cancers cells and immune cells collectively to spice up immune-mediated tumor killing. Lewis talked about bispecific antibodies with trastuzumab as one arm and both a T-cell engager, similar to an antibody concentrating on CD3, or a pure killer-cell engager, similar to an antibody concentrating on CD16, as the opposite arm.
“All of this actually reveals that trastuzumab has laid the background for creating antibody-based therapies towards HER2-positive cancers,” Lewis mentioned.
However what occurs when sufferers develop resistance to present HER2-targeted therapies? HER2 usually retains its robust expression regardless of now not driving the tumor, defined Gregory Frost, PhD, chairman and CEO of Exuma Biotech.
“Whereas the biology might change, the argument is that, in some instances, the presence of HER2 by means of amplification nonetheless stays, to go away it doubtlessly as a viable goal for different modalities of remedy,” Frost mentioned.
Frost and colleagues have been creating a CAR T-cell remedy that targets HER2—a tough job contemplating the baseline ranges of HER2 expression in lots of regular tissues. One among their designs is a “logic-gated” CAR T cell that solely assaults targets at a low pH, similar to within the tumor microenvironment.
In preclinical fashions, the cells promoted tumor regression whereas sparing regular tissues. These information have spurred a medical trial to check these CAR T cells in sufferers with metastatic stable tumors that specific HER2. Whereas medical exercise information stay immature, sufferers handled on the highest dose stage confirmed proof of CAR T cells circulating within the blood in addition to preliminary hints of tumor shrinkage.
“What we’d prefer to conclude is that, if HER2 stays amplified and accessible, mobile remedy approaches may someday present us one other arrow within the quiver for HER2-amplified malignancies,” Frost mentioned.
To view the unique FDA press releases for approvals issued between 2006 and 2016, try the FDA’s Hematology/Oncology Approvals & Security Notifications archive web site. To remain abreast of latest FDA approvals for most cancers indications, together with these for HER2-expressing malignancies, go to the AACR FDA Approvals web page