ctDNA Advances Perpetuate Progress Achieved With Osimertinib in EGFR+ NSCLC

Balazs Halmos, MD, MS

The emergence of the third-generation EGFR TKI osimertinib (Tagrisso) as the frontline standard of care in EGFR-mutated non—small cell lung cancer (NSCLC) has resulted in impressive survival benefits for patients, according to Balazs Halmos, MD, and the validation of circulating tumor DNA (ctDNA) testing in the up-front and acquired resistance settings has further helped to improve outcomes.

Frontline treatment with osimertinib was found to improve overall survival (OS) by 6.8 months compared with erlotinib (Tarceva) or gefitinib (Iressa) in patients with metastatic EGFR-mutant NSCLC, according to updated data from the phase III FLAURA trial. The median OS with osimertinib was 38.6 months (95% CI, 34.5-41.8) versus 31.8 months (95% CI, 26.6-36.0) with standard TKI therapy, translating to a 20% reduction in the risk of death with osimertinib (HR, 0.799; 95% CI, 0.647-0.997; P = .0462).¹

In April 2018, based on earlier data from FLAURA, the FDA approved osimertinib as a frontline treatment for patients with NSCLC whose tumors harbor EGFR mutations, either exon 19 deletions or exon 21 L858R substitution mutations. Osimertinib has since become the frontline standard of care for this patient population.

“Through these experiences, we've also learned about the need for repeated molecular testing, which is now greatly facilitated by the introduction of ctDNA technology,” said Halmos. “We’ve seen validation of ctDNA testing, both in the up-front setting to document the presence of EGFR mutations, as well as in the documentation of resistance mechanisms, such as EGFR T790M, and other mechanisms that we see with the introduction of osimertinib as the standard preferred frontline agent.”

Several research efforts are dedicated to overcoming the issue of resistance in patients who receive osimertinib in the first-line setting, according to Halmos. One particular area of interest is combining other agents into the frontline treatment of this patient population. For example, the phase III FLAURA2 trial (NCT04035486) will examine the use of osimertinib with or without chemotherapy as first-line treatment of patients with EGFR-mutated NSCLC.

Additionally, a phase I/II study is examining the combination of osimertinib plus bevacizumab (Avastin) in the up-front treatment of patients with EGFR-mutant NSCLC. Results showed that the overall response rate with the combination was 80%, which included 39 partial responses, 9 cases of stable disease, and 1 patient who was not evaluable. The median progression-free survival (PFS) was 18.4 months with the combination. The hazard ratio for the PFS at 1 year with osimertinib/bevacizumab was 0.76, while the goal was 0.70; furthermore, the hazard ratio for OS at 1 year was 0.91.²

In an interview during the 2020 OncLive^® State of the Science Summit on Lung Cancer, Halmos, director of Thoracic Oncology and Clinical Cancer Genomics at the Montefiore Albert Einstein Cancer Center, discussed the implications of the emergence of osimertinib in the frontline treatment of patients with EGFR-mutated NSCLC, the efforts being made to address resistance to the third-generation EGFR TKI, and the promise of ctDNA in the space.

OncLive: How has treatment for patients with EGFR-mutated NSCLC evolved over the years?

Halmos: Dramatic progress has been made in the management of patients with EGFR-mutated lung cancers, since [that mutation] was first recognized about 15 years ago. We learned that about 10% to 15% of our patients with advanced NSCLC will [have tumors that] harbor recurrent activating EGFR mutations, most commonly exon 19 deletions or [exon 21] L858R [mutations]. We identified this patient subset as one that is highly responsive to targeted therapy with EGFR TKIs. Since that time, we have developed several generations of EGFR TKIs and we also learned that targeted therapy can be very successful. However, acquired resistance is a recurrent issue that basically blocks the long-term durable benefits of these classes of compounds.

One key discovery earlier on was the understanding that most patients who receive a first- or second-generation TKI have very particular resistance mutations, such as EGFR T790M. We’ve since been able to develop third-generation EGFR TKIs, such as osimertinib, that are able to overcome that dominant resistance mechanism. In fact, the recently presented and published FLAURA study showed us that this third-generation drug that was specifically developed to address this key resistance mechanism, does, indeed, outperform our earlier-generation agents. As such, [osimertinib] is currently the standard, or preferred, frontline treatment for [patients with] EGFR-mutated lung cancer.

Although osimertinib was developed to overcome key resistance mechanisms, patients who are receiving this agent in the frontline setting are inevitably developing resistance to this agent as well. Could you discuss the efforts being made to address that challenge?

Osimertinib has shown not just benefits regarding PFS and OS over earlier-generation compounds, but also great specificity and less toxicity. [We are treating patients with an] ideal frontline molecule upon which we can work to improve outcomes of our patients; osimertinib is a very convenient, nontoxic, and effective compound.

We now need to understand why this is a good standard of care. Additionally, we know that osimertinib is still limited due to the fact that predictably, resistance will develop over time [in patients who receive this agent]. We’re increasingly learning more [about the development of] resistance to osimertinib; [we believe] this can be [due to] many pathway mechanisms, including second mutations and different types of histological transformation and bypass mechanisms.

While we have developed new strategies to address some of these resistance changes, we also need to recognize that offering combinations up front might help us minimize the development of resistance, and thus, help us achieve the best possible outcomes for our patients. With that in mind, a new wave of clinical trials [are launching that] my colleagues should be aware of.

These trials are incorporating other agents in addition to frontline EGFR TKIs; this includes antiangiogenic agents such as bevacizumab or ramucirumab (Cyramza), or conventional chemotherapy. [We believe these approaches might yield] significant benefits, such as PFS prolongation, and with chemotherapy, [we will] actually see OS improvement as well, in the context of first-generation EGFR TKIs.

Could you expand on some of the studies examining osimertinib combinations?

We have many ongoing studies in which investigators are attempting to exploit the findings [we have seen with] osimertinib. For example, the phase III FLAURA2 study is evaluating osimertinib with or without chemotherapy as first-line treatment in patients with EGFR-mutated NSCLC. Additionally, ECOG will open a study that will examine osimertinib with or without bevacizumab; this will be one of the more important national studies for us, as a field, to complete.

We want to invest in these combinations to improve outcomes even further for this subset of patients who already benefit from the treatment advances [that have been made in recent years]. We also want to [enhance what we know about] biomarkers to [improve] how patients [are] selected for certain treatments. For example, we want to use more extended molecular testing up front to better understand concurrent molecular abnormalities, define [a patient’s] prognosis, and [better recognize] benefits [of a particular treatment for our patients].

Even more importantly, [we want to further investigate] ctDNA-based strategies to address treatment benefits of combinations so that we can have surrogate biomarkers. For example, [an emerging] ctDNA test is looking at whether, for example, the mutant DNA might disappear from the circulation at different rates with different combinations; this might provide us with an early signal [pointing us to] which combination [we should] invest in as opposed to having to wait 4, 5, or 6 years for these large clinical studies to mature. We want to keep investigating these treatment strategies, evaluating combinations, and looking for better biomarkers; this is our focus as a field. However, fortunately, we have already accomplished a lot [in this space] and we have a great foundation for us to build upon.

As you mentioned, ctDNA is a key component in the care of patients whose tumors harbor molecular abnormalities. Could you expand on the advantages of these tests and some of the barriers still faced with their use?

ctDNA technology has already yielded some great advances for our field. We can utilize ctDNA technology in a validated fashion for molecular testing up front in the context of treatment selection for patients with metastatic NSCLC; this is not just for EGFR [mutations], but all the other molecular markers that we know we can target now, such as ALK, ROS1, RET, NTRK, MET exon 14 skipping, etc.

Now, we have multigene platforms for ctDNA, which have a high but not perfect yield to detect these molecular alterations. Of course, there are pros and cons with this technology. We can detect [alterations] in about 70% to 80% of patients with metastatic lung cancer, but in 20% to 30% [of patients], ctDNA does not yield a molecular biomarker in a diagnosis. We also need to recognize that ctDNA testing can yield false-positive information emerging through clonal hematopoiesis of indeterminate potential, which is an increasingly important area to focus on, especially in an elderly patient population.

ctDNA technology is also validated in the acquired resistance setting. I mentioned the example of EGFR T790M; ctDNA technology can be quite successful with a yield of 60% to 80% to detect this secondary alteration and align patients to switch treatments without the need for an invasive biopsy. In the context of osimertinib, ctDNA can also help with other acquired resistance alterations, such as MET amplification, for example. However, a shortcoming is that ctDNA is currently not yet capable of addressing the other type of resistance alteration called histological transformation.

We’re noticing that [with] osimertinib, a fairly high frequency of these histological transformations, most commonly small cell, but also squamous and sarcomatoid transformation [occur]; this is important to be aware of, since for example, small cell transformation needs to be treated separately with small cell—based chemotherapy regimens. Although there’s validation [for this testing] in both contexts, some shortcomings exist that a clinician will need to remember.

Novel uses for ctDNA [continue to emerge] and [that knowledge] will continue to expand as we become more familiar [with this approach] and more comfortable with some of its uses. Additionally, technological platforms appear to be rapidly advancing in terms of their sensitivity and costs appear to be coming down as well.

As I mentioned, an interesting use [of ctDNA] in this context is [emerging], where you could potentially identify the efficacy of a novel treatment just by monitoring the changes in ctDNA. In some contexts, it appears that the ctDNA changes can precede imaging changes [and provide] earlier assessments of treatment responses; as such, it might potentially be an even more powerful surrogate of long-term benefits of our molecular treatments, so there’s great promise [with the use of ctDNA] in that context as well.

References

1. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30(suppl 5; abstr LBA5_PR):v914-v915. doi: 10.1093/annonc/mdz394.076
2. Yu HA, Kim R, Makhnin A, et al. A phase 1/2 study of osimertinib and bevacizumab as initial treatment for patients with metastatic EGFR-mutant lung cancers. J Clin Oncol. 2019;37(suppl 15; abstr 9086). doi: 10.1200/JCO.2019.37.15_suppl.9086