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University of California, San Francisco
San Francisco, California
Matthew Gubens, MD, MS, has disclosed that he has received funds for research support paid to his institution from Celgene, Merck, Novartis, OncoMed, and Roche and consulting fees from AstraZeneca, Beyond Spring, Boehringer Ingelheim, Bristol-Myers Squibb, Inivata, and Takeda.
In this commentary, I present my perspective on current best practices in the treatment of patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC), with thoughts on biomarker testing, optimal choice of first-line therapy, and considerations for what to do at progression.
Biomarker Testing in Advanced NSCLC
In the setting of advanced NSCLC, it is critical to complete biomarker testing for all patients because the genotype of their disease will guide optimal treatment decisions. Although we have a sense of which patients are more likely to have an EGFR activating mutation, including never smokers, women, people of Asian descent, and those with adenocarcinoma, we do sometimes identify patients with EGFR mutations who do not fit these demographics, so it has become important to test everyone at diagnosis for this and other targetable alterations.
An EGFR mutation can readily be detected by analysis of either liquid or tissue biopsy. This is one of the driver mutations in lung cancer that is very faithful in liquid biopsies, so if the quantity of a patient’s initial tissue biopsy is insufficient or you need to expedite testing, a liquid biopsy is a very efficient way to look for an EGFR-activating mutation in a patient with high pretest probability of having this mutation.
When analyzing test results, it is important to understand that not all EGFR mutations are created equal. As we will discuss next, the canonical mutations, EGFR exon 19 deletion and exon 21 L858R mutation, can be effectively targeted with approved EGFR TKIs, and several noncanonical mutations, such as exon 21 L861Q, are also susceptible to these agents. We also identify exon 20 insertions in this same demographic of patients, but unfortunately, currently approved EGFR TKIs at standard doses are not effective in this setting.
Treatment Options for Newly Diagnosed EGFR-Mutant NSCLC
For a patient with newly diagnosed metastatic or stage IV NSCLC with an EGFR activating mutation, I usually prescribe osimertinib over the first-generation (ie, erlotinib and gefitinib) or second-generation (ie, afatinib and dacomitinib) EGFR TKIs. Data from the phase III FLAURA trial showed superior survival with osimertinib vs erlotinib or gefitinib in patients with untreated advanced NSCLC and a canonical EGFR mutation (median OS: 38.6 vs 31.8 months, respectively; HR: 0.80; P = .046). Osimertinib also has superior central nervous system (CNS) penetration and efficacy, which is important for a disease where brain metastases are common, as well as a favorable tolerability profile. There have been recent FDA approvals of combination therapy with early-generation EGFR TKIs and VEGF inhibitors (eg, erlotinib plus ramucirumab), but single-agent osimertinib remains the treatment of choice for most of our patients.
As I mentioned above, advanced NSCLC with an EGFR exon 20 insertion is not generally responsive to EGFR TKI therapy at standard doses, including osimertinib. There has been some interesting work in clinical trials trying to address the unmet need for effective therapies for these patients, and we are excited to now be seeing some positive results.
The first drug to be tried in this setting, poziotinib that was designed to target exon 20 insertions in both EGFR and HER2, has shown a reasonable response rate in early clinical trials, but the duration of response was brief and the toxicity profile included very significant rash, among other adverse events. More recently, mobocertinib, an EGFR TKI with special binding properties to exon 20 insertions, and amivantamab, a bispecific antibody that targets EGFR and MET, have also shown benefit as single agents in patients with EGFR exon 20 insertion–positive disease. Off label, we have seen some limited benefit with the combination of an EGFR TKI and an EGFR monoclonal antibody. A publication several years ago showed benefit with the combination of afatinib and cetuximab, but the dermatologic toxicities of this regimen were significant. This is an area to watch, and I believe there will be approvals in the future for this subset of patients.
Monitoring for Adverse Events With Osimertinib
Osimertinib is more tolerable than earlier-generation EGFR TKIs, but it is still important to educate patients about the risk of known EGFR on-target adverse events, such as rash and diarrhea. I typically schedule a toxicity visit and do laboratory tests 2-3 weeks after a patient has started treatment and then get initial imaging at 6‑8 weeks to determine if there is a response. If there is a benefit, I continue imaging every 2‑3 months thereafter.
There are also some more unusual adverse events with osimertinib that I like to follow, such as those related to cardiac health. I order a baseline ECG and another after some period of treatment to check for QTc prolongation. There is also a small risk of congestive heart failure, so I order a baseline transthoracic echocardiogram to make sure I have a baseline ejection fraction in place to compare against if there are signs or symptoms of CHF, which, in my practice, is the only situation when I would repeat this test.
What to Do for Progression on Osimertinib: Indolent or Oligometastatic Disease
When patients are being followed and we observe progressive disease, it is important to remember that not all progressive disease is the same. For patients with very indolent progression, on the order of millimeters, and who are asymptomatic, I extend their time on osimertinib but reduce the interval between imaging.
For oligoprogression, where a patient has one to a few areas of growth while other sites of disease remain under control, I consider local therapy to treat those tumors—typically radiation, but in selected cases, even surgery. When a patient has a single area of progression, especially when that tumor is the primary tumor, I definitely consult with my radiation oncology colleagues.
What to Do for Progression on Osimertinib: Systemic Disease
With global or systemic progression, there is enough disease burden to warrant a change in therapy. At this point, it is my practice to do a biopsy to look for actionable resistance mutations. I will biopsy either a progressing lesion (not necessarily the most conveniently reached) to establish the biology of the tumor or a liquid biopsy to get a sampling of the entire tumor burden. We have been learning a lot more about mechanisms of resistance to first-line osimertinib, and some viable options for treatment in this setting are beginning to emerge, a few of which I will mention below. However, I would first like to highlight that the relapsed setting is always an opportunity to consider enrolling your patients on a clinical trial if available in your area.
Small Cell Transformation
One mechanism of resistance to osimertinib is small cell transformation. This is a very aggressive form of progression that can be unifocal or multifocal. When looking at the tissue biopsy by IHC, it morphologically looks like the tumor has changed from NSCLC to small-cell lung cancer (SCLC). The genomic profile might also reflect this, including RB1 and P53 mutations that are typical of SCLC, along with the original EGFR mutation. This change is not as obvious on liquid biopsy, so with aggressive progression, I prefer to do a tissue biopsy. My next line of therapy for these cases is a SCLC‑focused chemotherapy regimen, such as platinum plus etoposide. After chemotherapy, another biopsy will often show a return to NSCLC morphology and loss of any SCLC-related genetic changes.
MET amplification is another common resistance mechanism to first-line treatment with osimertinib but is also often observed in NSCLC at diagnosis. We have increasing data showing good response rates from a variety of combination trials either with EGFR TKIs plus MET TKIs or, more recently, EGFR TKIs plus bispecific antibodies to both EGFR and MET after initial progression on osimertinib. Although these approaches are not yet approved, the data are compelling enough that if I see high (3+) MET amplification at the point of resistance, I do sometimes add a MET TKI to continued osimertinib.
Chemotherapy Options for Systemic Progression
If I do not identify small-cell transformation or a clear rationale to use an EGFR TKI combination, this is when I use a systemic chemotherapy regimen. The standard chemotherapy regimen for NSCLC is a platinum doublet, and I usually give carboplatin/pemetrexed with bevacizumab for 4 cycles followed by pemetrexed and bevacizumab maintenance.
Although it might be tempting to consider using the combination of carboplatin, pemetrexed, and pembrolizumab, which has become our first‑line regimen of choice for the treatment of nonsquamous NSCLC in the absence of a driver mutation, it should be noted that patients with EGFR-mutated disease were excluded from the phase III KEYNOTE-189 on which the approval of this regimen was based. In fact, we do not have a good sense of how effective immunotherapy in combination with chemotherapy is for treating these patients. We will have to wait to see the results of ongoing trials emulating the carboplatin, pemetrexed, and pembrolizumab approach in the setting of EGFR-mutant disease that is resistant to EGFR TKI therapy.
Another provocative approach to consider in the setting of EGFR TKI resistance would be the IMpower150 regimen. The IMpower150 trial evaluated a chemotherapy plus immunotherapy approach using carboplatin, paclitaxel, bevacizumab, and atezolizumab. A small set of patients in this study had EGFR mutations and progressive disease after prior therapy with EGFR TKIs. There was a benefit to chemotherapy, bevacizumab, and immunotherapy vs chemotherapy/ bevacizumab alone in these patients, but it was not one of the primary endpoints of the trial, and the FDA has not yet approved this regimen for these patients.
Considerations for Progression in the CNS
EGFR-positive NSCLC often metastasizes to the brain and sometimes even to the leptomeninges. Although osimertinib is a very CNS‑active drug at standard doses, we sometimes see brain progression even when systemic disease is controlled. In those cases, we talk as a multidisciplinary team about whether stereotactic radiation, whole‑brain radiation, or dose intensification of the osimertinib might be warranted, especially in a leptomeningeal setting. In the phase I BLOOM trial, osimertinib at a dose of 160 mg once daily conferred benefit to patients with disease in the leptomeninges.
The Future of Osimertinib Therapy: EGFR TKI Therapy for Early-Stage NSCLC?
In late 2020, osimertinib was approved by the FDA for treatment of early-stage NSCLC in the adjuvant setting. This approval was based on results from the phase III ADAURA trial, which showed a clear disease‑free survival benefit with up to 3 years of osimertinib vs observation alone. Median disease-free survival for patients with stage II/IIIA NSCLC was not reached with osimertinib vs 19.6 months with placebo alone (HR: 0.17; P < .0001). Although the primary endpoint of the trial was investigator-assessed disease-free survival in patients with stage II/IIIA disease, stage IB patients were also included in the study, and the FDA label does not mention stage.
Although this is exciting, I do not think it displaces the important role of chemotherapy in the curative treatment of patients with early-stage NSCLC, especially with stage IB and greater disease. After resection, I still offer 4 cycles of platinum-based chemotherapy before considering adjuvant osimertinib. It also remains to be seen what the resistance situation will be for patients who progress on or after adjuvant osimertinib treatment. We will learn more in the coming years, especially whether adjuvant osimertinib imparts an OS benefit, but data already show a clear reduction in progression after resection and in the development of brain metastases.
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