Tracing Steps of Clinical Research in Lung Cancer

Herbst is Ensign Professor of Medicine (medical oncology) and professor of pharmacology, chief of medical oncology, and associate cancer center director for translational science at Yale Cancer Center and Smilow Cancer Hospital, in New Haven, Connecticut, as well as cochair of the 22nd Annual International Lung Cancer Congress®, hosted by Physicians’ Education Resource, LLC (PER®).

Compared with decades ago, survival times for patients with lung cancer have dramatically increased, thanks to the introduction of targeted therapies and immune checkpoint inhibitors. Since these initial advances, investigators have focused on ways to further these results, by overcoming mechanisms of innate and acquired resistance across modalities and by discovering additional biomarkers of response.

Even as therapies garner increasingly favorable efficacy profiles, it will be imperative to identify the barriers to response that continue to be seen in certain subsets of patients. To discuss the research path that led the field to this point, ONCOLOGY® sat down with Roy S. Herbst, MD, PhD, who is Ensign Professor of Medicine (medical oncology) and professor of pharmacology, chief of medical oncology, and associate cancer center director for translational science at Yale Cancer Center and Smilow Cancer Hospital, in New Haven, Connecticut, to shed light on the topic.

Herbst is the program cochair of the 22nd Annual International Lung Cancer Congress®, hosted by Physicians’ Education Resource, LLC (PER®), to be held July 29 to 31, 2021. The meeting will cover emerging topics in lung cancers and will review continuing trends in the treatment paradigm.

Q: During your career, lung cancer has become one of the most rapidly progressing disciplines in oncology. What has changed in that time?

Herbst: I started in this field in 1994. At that time, I was a fellow at Dana-Farber [Cancer Institute]. What we had was cytotoxic chemotherapy, and it was pretty toxic with little benefit. There was no real plateau [in the survival curves], or no tail on the curve, so to speak.

I had trained in research. Not much progress had [occurred in the field when I started]. We were seeing some effects with bringing chemotherapy to the early stages of disease with radiation, but it was clear we needed to do more.

I started to see patients with lung cancer at Dana-Farber and I got involved with some early clinical trials. Soon thereafter, I was recruited to [The University of Texas] MD Anderson Cancer Center in Houston. [I was involved with] early trials with tyrosine kinase inhibitors, against EGFR, the first one being ZD1839 (gefitinib; Iressa). I was very interested in that pathway scientifically, and I became the lead investigator on those trials at MD Anderson. They were open in lung, breast, and prostate cancer, and they worked really well in lung. We saw about 1 in 10 patients responding, and we started to see these drugs were working. We treated patients and we searched for the biomarker. We realized that those patients who had not smoked to date did best and, of course, around 2004, several groups in Boston, using samples from trials that we had actually helped design, found a specific mutation in the EGFR gene in patients who responded well.1 The rest is history.

From then on, we saw such great advances in lung cancer with targeted therapy. Then around 2009 to 2010, we saw immunotherapy [emerge]. Using science to guide therapy and bring the therapy from the lab to the clinic has dropped the death rate in lung cancer historically.

Q: What is it like for you to be a part of that kind of revolution?

Herbst: We’ve always treated patients with compassion. We’ve always used multimodality care, and when you can, surgery and radiation with medical oncology, or chemotherapy. We’ve been able to raise the bar, [but it’s] still not nearly far enough. Many patients still die from this disease.

But the fact that we could take scientific discoveries—sometimes with biomarkers, so we can understand who benefits [more] than others, and learning more about the science in the lab first— and [translate that to] targeted therapy and immunotherapy is fantastic, I think. It speaks to how we are bridging the gap and helping people live longer with this disease. That’s what gets me up every morning: seeing the science translated to the patient.

Q: In frontline advanced disease, treatment breaks down along 2 tracks: targeted therapy, if a driver mutation is present, or immunotherapy. Will that approach continue, or is there a setting in which immunotherapy would displace targeted therapy?

Herbst: Right now, we look for driver mutations. While the response rates are high [with targeted therapy], the recurrence will occur at some point because of resistance to those drugs. But right now, it’s pretty clear that if you have a target, you use the target first, and then immunotherapy is used more in patients who don’t have those targets. Many of them are more likely to be smokers, and they have [higher] tumor mutational burden.

That said, the fact that we don’t cure anyone with targeted therapy, and [the fact that] these patients do [develop recurrent disease], begs this question: Can we use either standard checkpoint PD-1/PD-L1 or other immunotherapy in these patients to try to have a better effect? These are all things that we’re looking at now in the lab and in the clinic.

Q: How do you break through and expand the benefit of immunotherapy for more patients?

Herbst: You have to ask [whether there’s] primary resistance or acquired resistance. [An example of] primary resistance is that even with PD-L1–high tumors, [when patients are treated] with pembrolizumab [Keytruda], only 50% [respond]. Why are those other 50% negative? We have to look at those 50% and understand what else is happening. What are the regulatory mechanisms going on even though we see PD-L1 [expression]?

[Then, some patients] initially respond to immunotherapy, and then they become refractory; [in other words], they’ve responded and then they stopped responding. What’s going on? That’s the group for whom we have to look at tumor images. Are there new mutations? Have they lost MHC1? We are uncovering resistance mechanisms. What we do is we take those models of those patients’ tumors and put them into mice. [When] we have a mouse model of a patient’s tumor that became resistant, then we can start to look at innate immune mechanisms or other ways to activate the immune system [in that patient]. That’s what keeps me going: trying to find new combos, new immunotherapies that use biology to promote even better therapy.

Q: What is the latest thinking about the best way to use liquid biopsy vs tissue testing?

Herbst: I clearly want tissue testing for diagnosis; I don’t think you should make a histology [decision] based on a liquid biopsy. But after that, if [the test is] sensitive enough and assuming enough tumor is being shed, the [liquid] biopsy is a very good way to measure mutational status. If the liquid is negative, I would look to tissue, [the test of] which is going to be more sensitive.

Q: How did you become interested in improving diversity in clinical trials? Why, in your experience, is it so difficult to get patients of color from underserved communities to participate?

Herbst: Diversity coordinates with access. We certainly want to make sure everyone has access to clinical trials. I think that by putting someone on a clinical trial, it forces the clinician to think about the standard of care. I think care is improved in settings where there are clinical trials. You [also] want to have experience in those minority populations for the [disease] activity, although I don’t believe that in most cases there’ll be much difference. You want there to be trust of the community and the drugs. Diversity is important. Diversity is important in the workplace. It’s important in clinical trials [and] supported in all aspects of life.

Q: Of all your research, what results do you think have had the most impact?

Herbst: My most impactful work is the use of EGFR inhibitors in lung cancer: understanding of their use, of toxicity, the response, bringing those drugs to the clinic, and understanding biomarkers involved in their use. Then, of course, bringing it all the way to phase 3 [trials of osimertinib (Tagrisso) in untreated patients as adjuvant] therapy with highly positive response. Those results were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program plenary and in the New England Journal of Medicine.^2,3

Financial Disclosure: The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

REFERENCES

1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139. doi:10.1056/NEJMoa04093

2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation-positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(18 suppl 18):abstr LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5

3. Wu Y-L, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071