Robert L. Ferris, MD, PhD

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.

Articles

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. 

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

Even during times of coronavirus disease 2019, exciting cancer research is showing us the path forward with new combinations in difficult-to-treat cancers. Thankfully, the virtual American Association for Cancer Research (AACR) Annual Meeting 2020 continued to transmit exciting findings, including some from clinical trials. Grant McArthur, PhD, from the Peter MacCallum Cancer Center in Melbourne Australia, presented the IMspire150 trial (NCT02908672), whose results showed that atezolizumab (Tecentriq) combined with vemurafenib (Zelboraf) and cobimetinib (Cotellic) improved progression-free survival (PFS) and extended duration of response compared with vemurafenib and cobimetinib alone, which target BRAF and MEK. This phase 3 trial enrolled patients with BRAF V600–mutant advanced melanoma, in which a combination of BRAF/MEK inhibition demonstrated substantial responses. The sweet spot of immuno- oncology, of course, is enhanced durability and overall survival. Thus, combining atezolizumab, a PD-L1 inhibitor immunotherapy, with targeted therapies demonstrated a median PFS of 15.1 months compared with 10.6 months with the targeted agents alone.

Likewise, another PD-L1 combination pairing durvalumab (Imfinzi) with the PARP inhibitor olaparib (Lynparza) was used with neoadjuvant paclitaxel to increase pathologic complete response (pCR) in patients with high-risk, HER2-negative, stage II/III breast cancer compared with paclitaxel chemotherapy alone. This trial was one of the arms of the phase 2 I-SPY 2 study (NCT01042379), also presented at the virtual AACR meeting. The combination of immune checkpoint therapy with a PARP inhibitor is driven by blocking nucleotide and base excision repair to Robert L. Ferris, MD, PhD Director Hillman Cancer Center University of Pittsburgh Medical Center Pittsburgh, PA increase mutational and neoantigen burden. Thus, DNA fragments may also activate the intracellular inflammatory STING pathway. PARP inhibition can also increase expression of PD-L1 in breast cancer cells. As such, the rational design of durvalumab and the PARP inhibitor was tested in this arm of the I-SPY 2 multicenter neoadjuvant trial. This innovative, response-adaptive randomization trial compared multiple experimental arms with a shared control arm using a Bayesian predictive probability. The objective response rate was 63.3% with the combination, resulting in a pCR rate of 47% versus 27% with paclitaxel alone. This has an estimated probability of a superior experimental arm to chemotherapy alone of 98% in all subsets of patients. Pushing the cell therapy field forward, Caron A. Jacobson, MD, medical director, Immune Effector Cell Therapy Program at the Dana-Farber Cancer Institute and assistant professor of medicine, Harvard Medical School, in Boston, Massachusetts reported the findings of the ZUMA-6 trial (NCT02926833), which evaluated chimeric antigen receptor (CAR) T-cell therapy combined with atezolizumab in patients with refractory diffuse large B-cell lymphoma, at the AACR conference. The trial was blocking PD-L1 on active CAR T cells at different time schedules and demonstrated safety and tolerability.

In all, these 3 exciting trials combining PD-1 or PD-L1 inhibition with targeted therapy, chemotherapy, or immune cell (CAR T-cell) therapy bode well for evolving advances with this tolerable class of agents.

"In all, these 3 exciting trials combining PD-1 or PD-L1 inhibition with targeted therapy, chemotherapy, or immune cell therapy bode well for evolving advances with this tolerable class of agents."

Robert L. Ferris, MD, PhD | Authors

Articles

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

Anti–PD-1/PD-L1 Immunotherapies Continue to Impress in Unique Combinations