Robert L. Ferris, MD, PhD

In reviewing the recent progress from the European Society of Medical Oncology Breast 2021 Virtual Congress, a number of abstracts presented data that focused on diagnostic, therapeutic, or other biological investigations around the HER2 receptor and its associated growth factor pathway. It struck me as exciting and gratifying for the fi eld of biologically driven, precision oncology that the discovery of such a marker protein, the HER2 receptor and the ErbB family, is still a major area of investigation and fruitful benefit in the clinic for patients. 

The abstracts presented in this issue of 

 focus on neratinib (Nerlynx) as an irreversible HER2 inhibitor with therapeutic potential. Other research looked at the possibility of less intense trastuzumab (Herceptin), the anti-HER2 monoclonal antibody that has been approved for some decades, in the adjuvant setting.

Discoveries made in the mid-to-late 1980s by Drs Dennis Slamon and Stuart Aaronson involving the HER2 family have led to a number of advances: a subset of patients eligible for targeted therapies, biological tumor classification, and even antibody-drug conjugates, which deliver a payload using this targeted receptor for concentration of toxic chemotherapy. Indeed, genomic guidance based on mutations or copy number alterations is another way that we can diagnose and potentially track patients with circulating tumor DNA. So, looking back on the 30 to 40 years since the HER2 protein and its relevant oncogenic pathway were discovered, it is amazing that we are still actively investigating the therapeutic potential and the true evidence for precision oncology and biology-based cancer treatment.

It has taken some decades, but the identification of targets such as HER2 has enabled us to segregate cancers into different subtypes, develop novel therapeutic strategies, and eventually understand the biology distinguishing one group of patients from another. Furthermore, as we deploy our therapeutic weapons at the cancer cells, we need to have some specific target to shoot at—and this was one of the first. Understanding tumor heterogeneity and the role of individual pathways is commonplace now in the 2020s. However, thinking about how far we have come since the late 1980s reinforces that this is the correct path for translational science and many patients are benefiting. But what is equally intriguing is how much more we have to learn as clinical trials are still testing nuances of subgroups defined by HER2 in breast cancer and the ErbB family across many other solid tumors. The path is long, but progress is happening faster and faster.

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It has taken some decades, but the identification of targets such as HER2 has enabled us to segregate cancers into different subtypes, develop novel therapeutic strategies, and eventually understand the biology distinguishing one group of patients from another, says Robert L. Ferris, MD, PhD.

After More Than 30 Years, Research on HER2 Continues to Expand Our Understanding of Cancer 

One of the most exciting and successful historical demonstrations of translational immunotherapy is the development of monoclonal antibodies. Since the early 1900s when Paul Ehrlich, MD, envisioned these agents as “magic bullets,” monoclonal antibodies have been studied, coming into their own because of investigators’ ability to isolate and produce them in large-scale batches for research and clinical applications.

Large-scale batches for research and clinical applications. In 1984, Niels K. Jerne, MD; Georges J.F. Köhler, PhD; and César Milstein, PhD, who had discovered the principle for production of monoclonal antibodies, were awarded the 1984 Nobel Prize in Physiology or Medicine. Monoclonal antibodies demonstrated their potency and exquisite specificity for a particular target. An example is the linkage of chemotherapy as a payload onto the anti–HER2-specific antibody trastuzumab (Herceptin). In 2013, the FDA approved trastuzumab emtansine (T-DM1; Kadcyla) for HER2-expressing breast cancers resistant to trastuzumab or taxane chemotherapy.

Subsequently, the discovery that monoclonal antibodies could block inhibitory immune checkpoint receptors, such as PD-1 and CTLA-4, led to the 2018 Nobel Prize in Physiology or Medicine being awarded to James P. Allison, PhD, and Tasuku Honjo, MD, PhD.

The most recent development involves the field of theranostics, which uses radiolabeled monoclonal antibodies to target a particular tumor selective protein. In this issue of Targeted Therapies in Oncology, we review a series of theranostic strategies for not only diagnostic imaging of disseminated disease using radiolabeled monoclonal antibodies, but also for modifying the dosage and radioisotope to deliver therapeutic antitumor doses of the radiation in a highly targeted fashion, even for systemically metastatic cancer (see pages 30-34). There are now several theranostic antibodies that target cancer, the most recent being prostatespecific membrane antigen for prostate cancer.

The next generation of monoclonal antibodies can increase their targets in a single molecule, which are bispecific and trispecific, harnessing multiple specificities. These multimeric antibodies effectively increase the local concentration of antibody in the tumor microenvironment and harness the biology of multiple pathways that can be targeted for inhibition or stimulation, leading to more effective cancer therapy. These are truly amazing times that couple deep knowledge of biology with protein engineering, embodying the “magic bullets” envisioned more than 100 years ago.

One of the most exciting and successful historical demonstrations of translational immunotherapy is the development of monoclonal antibodies, says Robert L. Ferris, MD.

Monoclonal Antibody Development Expands to Include Theranostics

It was certainly inevitable. In the wake of the enthusiasm around cancer immunotherapy trial results—with several positive trials presented annually at each American Society of Clinical Oncology (ASCO) meeting in more and more diseases over several years—setbacks have served as a grim reminder that our work isn’t finished. Recently, the mood has changed to realism and, in some cases, pessimism, as some large trials reported as negative despite high expectations for efficacy. Although earlier efforts in the targeted therapies field had known limited success, the various cancers, immunotherapy, and cancer vaccine field had lived through sine waves of excitement and failure. From 2013 onward, anti–CTLA-4 and anti–PD-1/PD-L1 therapies seemed to work in nearly every disease in which a trial was conducted.

We perhaps became overconfident. Then came the PD-1/IDO (indoleamine 2,3-dioxygenase) experience at ASCO 2018 with the surprising negative phase 3 trial in melanoma.

 In the field of immunotherapy, we had been used to disappointing trials. In this case, however, based on the biology, it should have worked. Recent phase 3 practice-changing trials have increasingly been reporting negative. So what is the problem? And what can we learn?

In the past year or so, we have seen negative trials with anti–PD-L1 plus taxane in aggressive breast cancer, negative combinations including PD-L1 plus CTLA-4 targeting in head and neck cancer, and surprisingly, a lack of efficacy when adding anti–PD-L1 to chemoradiation in a trial that included an entire year of adjuvant avelumab (Bavencio). At least the 1 year of avelumab, like the PACIFIC trial in non–small-cell lung cancer, should have salvaged any biologically inert effect of adding the antibody during chemoradiation.

So are the setbacks a matter of trial design—incomplete understanding of tumor cell and microenvironment biology? Or is it simply a technical defect in the study design and population eligibility? The secret and answer may lie in the populations enrolled and the method of enriching for likely responders.

An interesting lesson comes from the HRAS field, where 

-mutated but otherwise unselected patients were entered into a trial of tipifarnib, a farnesyltransferase inhibitor (FTI). The biology indicated that FTI inhibition would selectively work in 

-mutated cancers. However, the trials were negative, and the drug was put on the shelf. It was recently salvaged with an attempt to increase the fraction of high variant allele fraction (VAF)—in other words, those patients much more likely to benefit because 

was a “driver,” rather than a passenger, alteration. Data suggested that this approach of enriching high-responding patients is not simply a construct of biostatistical study design, but rather an existential question for drugs currently on the market or hoping to be so in various cancer types.

 Therefore, scientists and translational investigators need to go back to the laboratory, analyze data, and curate their specimens genomically and immunologically to ensure we understand whom we are entering into which trials and whether the biology enriches the likelihood of success.

So the field is bright with a seemingly never-ending list of novel agents and repurposed drugs targeting known and uniquely identified pathways. We stumbled upon PD-1 inhibitors nearly 10 years ago and are yet to find the next successor with pan-tumor activity. Cancer is complex, patients are heterogeneous, and the biology of tumor escape has had 10 or more years of lead time in the patient before the oncology community had a chance to introduce antitumor therapies in the context of prospective randomized trials. So we should not despair, but rather, beat the cancer at its own game—segmenting it into the biology of driver genomic and immunologic dependencies, identifying them with the most novel techniques available, and integrating these into tissue-intensive, patient-enriched clinical trials, with unique adaptive designs to rapidly identify resistance or response.

We need to leverage neoadjuvant preoperative clinical trials, with on-treatment biopsies, to identify dynamic biomarkers and therapy-directed changes in the tumor microenvironment. This combined with collaboration between academia and industry hold promise for moving to the next successful phase of oncologic therapies while also trying to shortcut the large multiyear randomized phase 3 trials of unselected patients relying on a battery of retrospective static, pretreatment biomarkers tested in paraffin. That got us to this point, but the challenge is to move to the next phase. Our patients demand it, and the field is prepared.

1. Long GV, Dummer R, Hamid O, et al: Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL.

2. Sternberg A. Tipifarnib yields 100% disease control in HRAS-mutant head and neck squamous cell carcinoma. Targeted Oncology™. December 3, 2019. Accessed September 16, 2020. https://bit.ly/2RycZu4

In the wake of the enthusiasm around cancer immunotherapy trial results—with several positive trials presented annually at each American Society of Clinical Oncology meeting in more and more diseases over several years—setbacks have served as a grim reminder that our work is not finished.

Lessons From Clinical Trial Setbacks Lead to Next Phase of Oncologic Advances

Two areas of science have been developing in parallel: precision oncology/genomics-based medicine and immuno-oncology/cancer immunotherapy. Exciting new knowledge and a more exquisite understanding of the role of tumor cell biology and the tumor microenvironment have driven both fields. This progress has resulted in the identification of receptor ligand targets at the cell surface for antibody therapies or dysregulated intracellular pathways, which small molecules for precision oncology can target.

However, these approaches now have unique and important clinical implications. First, key cancer immunotherapeutic targets, such as the PD-1, PD-L1, and CTLA-4 pathways, are targetable across many cancer types, and the mechanisms appear to be the same, thus expanding the number of candidates for treatment with those therapies. Oncologists, with their understanding of the PD-1/PD-L1 or CTLA-4 pathway, along with the immune checkpoint concept, can then apply that knowledge to a broad range of cancers in a relatively straightforward way.

In contrast, genomics-driven, precision oncology has the opposite effect, segmenting and subdividing cancers into smaller subgroups in which treatments are paired with genomic subtypes. This has led to an ever-growing and more extensive scientific demand on the community oncologist, who may not focus on a particular cancer type or be able to remain up-to-date on every new pathway or signaling network being targeted.

Indeed, drugs, such as the small molecule tipifarnib, have recently shown clinical activity in tumors with certain 

 mutational subtypes is a good example. Individual 

 mutations are paired with different drugs (G12C targeted by AMG 510) in various cancers, and this may occur in lung, pancreatic, and colorectal carcinomas, to name a few. Thus, although these are fascinating times with great potential clinical benefit for patients, community oncologists must attempt to keep up with early research, which is important but often gets into the weeds of the science and targetable pathways.

The complexity of these novel therapies and their tumor biology underpinnings raise even more concern during the coronavirus disease 2019 (COVID-19) pandemic because in-person continuing medical education (CME) meetings have gone online and may be harder to follow. Attending the American Society of Clinical Oncology, the American Association for Cancer Research, the Society for Immunotherapy of Cancer, and other specialty organization meetings is a staple for community oncologists trying to keep up with these fascinating advances with direct patient implications and treatment and management recommendations. We need to understand the impact this may further have on the oncology community because the pace of discovery has amplified the importance of understanding the science behind the new drugs as well as knowing how to use them safely and effectively. The community has underscored the loss of early detection through delayed screening during COVID-19. Now we must realize that unfulfilled CME interactions and information transfer may also be a consequence to overcome until we can return to large meeting rooms and lecture halls. The struggle to keep up with the pace of these exciting areas of translational and clinical oncology, in an effort to understand the targets as well as the specific targeted therapies, may be an impact of the COVID-19 pandemic.

Exciting new knowledge and a more exquisite understanding of the role of tumor cell biology and the tumor microenvironment have driven the fields of precision oncology/genomics-based medicine and immuno-oncology/cancer immunotherapy. 

Robert L. Ferris, MD, PhD | Authors

Articles

After More Than 30 Years, Research on HER2 Continues to Expand Our Understanding of Cancer

Monoclonal Antibody Development Expands to Include Theranostics

Lessons From Clinical Trial Setbacks Lead to Next Phase of Oncologic Advances

Educational Interactions Among Oncologists Remain a Subtle Loss During COVID-19 Pandemic