Modern Treatment Standards Require State-of-the-Art Molecular Profiling

Charu Aggarwal, MD, PhD, is the Leslye M. Heisler Associate Professor for Lung Excellence at the University of Pennsylvania’s Perelman School of Medicine and co-chair of the 6th Annual International Congress of Immunotherapies in Cancer™, hosted by Physicians’ Education Resource, LLC (PER®).

As more and more targeted therapy options emerge in the cancer space, investigators continue to see positive impacts on long-term outcomes. However, this wider, advanced, individualized range of treatment options that may be offered to patients requires more sophisticated molecular testing techniques.

In an interview with ONCOLOGY^®, Charu Aggarwal, MD, MPH, discussed this topic as it relates to her ongoing research, as well as how it may carry to other areas of oncology care outside of her area of expertise in the lung cancer space. She is the Leslye M. Heisler Associate Professor for Lung Cancer Excellence in the Department of Medicine at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia as well as co-chair for the 6th Annual International Congress on Immunotherapies in Cancer™, hosted by Physicians’ Education Resource, LLC (PER®).

Aggarwal spoke about how liquid biopsies, rather than invasive procedures, can help determine treatment prognosis. She also detailed how immunotherapy has evolved as a mainstay of treatment and how clinicians are now looking at adverse effects (AEs) as a positive sign of treatment efficacy.

Q: Can you discuss the benefits of liquid biopsies vs tissue sampling?

A: Molecular genotyping is becoming extremely important in non–small cell lung cancer. At least 9 biomarkers¹ must now be tested at initial diagnosis, and the gold standard for testing has been to use tissue-based testing. [However], it’s often a problem to get tissue because these biopsies are small and sometimes not enough tissue or not enough DNA [is present] on these samples. [So then] we asked, “Could we complement our ability to test for these mutations using tissue alone by adding in plasma-based sequencing?” We conducted a follow-up trial with about 300 patients here [at the University of Pennsylvania] and found that by adding plasma-based approaches, using 2 tubes of blood, we could get [results] relatively easier compared with tissue-based sequencing.² We were able to increase our detection of molecular alterations from about 20% to about 36%—a significant increase. This means that more patients were able to get targeted therapy, receive a drug based on their molecular profile, and have significant benefit. Patients were able to avoid chemotherapy or immunotherapy.

We are currently doing much more with liquid biopsies [and are] really looking at the dynamics of circulating tumor DNA [ctDNA], to guide whether patients are responding to treatment. If the ctDNA goes down, that gives us a sense, an indicator, that the therapy is working, [possibly] before we get a radiographic response, before I even get the CT scan. [Liquid biopsy] is an active area of research that I think will be extremely interesting.

Q: In other words, you can regularly draw blood to see how the therapy is progressing?

A: Exactly. That’s the point: We can [check progress] in a minimally invasive way.

Q: How can you learn so much through liquid biopsies for solid tumors in lung cancer?

A: Lung cancer is among the leading cancer subtypes where liquid biopsies are being used. That’s because a significant amount of ctDNA is shed into the bloodstream in patients with advanced disease. [Also], lung cancer has so many different [molecular, actionable] subtypes that now have targetable drugs. We can say [to a patient], “You have an EGFR mutation” or “You have a MET exon 14 [skipping] mutation—I’m going to give you a pill.” There is more actionability in lung cancer than in other diseases. However, breast cancer, gastrointestinal cancer, and genitourinary cancer are all now [using] liquid biopsies and expanding the space to utilize it in the clinical setting.

Q: Are we getting closer to being able to substitute liquid biopsies for tumor samples?

A: I think we are getting there. We’re not completely there, because we still need a few things from tissue samples. We can never characterize the cell type or the architecture of a tumor, which are still very necessary, with a liquid biopsy. Looking at tissue is still extremely important, no matter what. I think plasma or liquid biopsies will be essential to give us information about the rest of the tumor. In fact, it sometimes gives us a clearer picture of the heterogeneous nature of the tumor, so we can get a sense of the cells that may have more metastatic potential and may have a slightly different mutational profile. We can gather that [information] much better than we can with a single small biopsy.

Q: How can you determine how well a treatment is going?

A: The most obvious indication that [a treatment is working is] less tumor. However, we’re also looking at other things like methylation signatures, RNA sequencing, and changes in mutational profile over time that may help us eventually [determine how treatment is going].

Q: Can you discuss when to use targeted therapy vs immunotherapy to treat lung cancer?

A: We have learned a great deal about when to use targeted therapy in lung cancer. We need to know a patient’s molecular subtype. One way we [learn] that is by using both tissue and plasma sequencing, which is a must. Once we know the molecular subtype, the next question is how we utilize the information to guide therapy. In my mind, the question is not who should get chemotherapy, but who can avoid chemotherapy in this day and age. I feel that with the explosion of immunotherapy, we can now deliver immunotherapy safely with a survival benefit for most of our patients. There will always be a subset who don’t get immunotherapy, but the vast majority of our patients can, and we use PD-L1 testing to determine which patients can get immunotherapy alone. Again, that’s only for a small subset of patients; for [the rest, we’re still] using a combination of chemotherapy and immunotherapy.

Q: What have you learned about the mechanism of action for immunotherapies? Does that affect the strategy for deploying them against lung cancer?

A: The premise of immunotherapy is reactivating the immune system and harnessing the power of T cells during cancer treatment. We know that our T cells as well as our bodies are inherently programmed to fight cancer. However, cancer cells may express inhibitory molecules; these can then be inhibited using PD-L1 inhibitors, potentially creating the immune response again. That’s the premise: the immune activation that’s inherent in the immune system to fight cancer.

Q: What have we learned about managing immune-related AEs (irAEs)?

A: Many guidelines now help us with managing irAEs in a stepwise fashion, including guidelines from the National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the American Society of Clinical Oncology. I’d [like to] add that recent evidence suggests that the presence of irAEs in patients who receive immunotherapy may be related to better outcomes, depending on the grade of AEs. Preliminary data, at least, suggest that grade 2 and 3 AEs may be better in terms of predicting for an improved outcome to immunotherapy, which I think is very interesting. It’s reminiscent of the “old days” when we used to look at things like rash from EGFR inhibitors [to] tell us that the drug is working, [and] also that they are more likely to see a response.

Financial Disclosure: The authors have 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. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2021. Accessed September 2, 2021. https://bit.ly/3DGrtPb

2. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non–small cell lung cancer. JAMA Oncol. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.4305