CE / CME
Pharmacists: 1.25 contact hours (0.125 CEUs)
Nurses: 1.25 Nursing contact hours
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: September 30, 2022
Expiration: September 29, 2023
Edward B. Garon, MD, MS:
Moving on to a discussion about practice patterns in the setting of newly diagnosed metastatic disease, we asked in our survey, “In your practice, what frontline therapy are you using for most of your patients with newly diagnosed EGFR-mutant advanced NSCLC?” Unless otherwise stated, we are referring to patients with the classical, sensitizing EGFR alterations, exon 19 deletions, or the L858R substitution mutation.
Almost 90% of HCPs reported that they were most often using an EGFR TKI in patients with newly diagnosed EGFR-mutant advanced NSCLC, with 47% preferring the third-generation EGFR TKI osimertinib. Between 10% and 15% each reported use of the first-generation EGFR TKIs erlotinib or gefitinib, or the second-generation EGFR TKI afatinib as their preferred first-line EGFR TKI. One HCP each would give the second-generation EGFR TKI dacomitinib or an EGFR TKI combination, including erlotinib plus the antiangiogenic VEGF inhibitor bevacizumab and gefitinib plus chemotherapy.
The remaining approximately 10% of HCPs reported preferring chemotherapy with or without an immune checkpoint inhibitor or selected “other.”
Table 6. In your practice, what frontline therapy are you using for most of your patients with newly diagnosed EGFR-mutant advanced NSCLC?
Edward B. Garon, MD, MS:
The unanimous opinion of the panel was that osimertinib is the preferred SoC for patients newly diagnosed with NSCLC and an EGFR del19 or L858R mutation.15 Dr. Le, would you comment on why the experts are unanimous in this recommendation?
Xiuning Le, MD, PhD:
Osimertinib is the preferred frontline therapy for newly diagnosed EGFR-mutated advanced NSCLC because of the compelling efficacy and safety data observed in the registrational FLAURA trial, which compared osimertinib with a first-generation EGFR TKI (erlotinib or gefitinib) in patients with previously untreated advanced NSCLC adenocarcinoma that harbored EGFR exon 19 or L858R mutations.18
Xiuning Le, MD, PhD:
The trial met its primary endpoint of investigator-assessed PFS, with osimertinib achieving a median PFS of almost 19 months vs 10 months with the comparator EGFR TKIs.18 This translated to a significant 54% reduction in the risk of disease progression or death (P <.001). Frontline osimertinib also exhibited an OS benefit (HR: 0.80; P = .046),19 reinforcing it as our current first-line SoC in the frontline setting.
Furthermore, results from FLAURA showed that patients who had CNS metastases at baseline clearly did better on osimertinib than erlotinib or gefitinib, with a median PFS of 15.2 months vs 9.6 months, respectively (HR: 0.47; P < .001), suggesting osimertinib is more CNS penetrant.18 CNS progression events were also more common in patients receiving first-generation TKIs, at 15%, compared with only 6% with osimertinib.
Finally, most patients tolerate osimertinib very well. After almost 2 years of exposure, the safety profile of osimertinib was similar to the comparator agents, and some adverse events were improved.19
Edward B. Garon, MD, MS:
Thank you, Dr. Le.
Edward B. Garon, MD, MS:
Let’s shift gears to talk a bit about EGFR TKI combination therapy. As shown in Table 5, only a couple HCPs chose an EGFR TKI combination regimen, with no HCPs reporting that they use the FDA-approved combination of erlotinib plus the antiangiogenic VEGFR2 inhibitor ramucirumab in the first-line setting for EGFR-mutated advanced NSCLC. This was not entirely surprising, considering that current practice and recommendations clearly favor the use of single-agent EGFR TKI therapy with osimertinib in the first-line setting for EGFR-mutated advanced NSCLC.
That being said, preclinical and clinical data suggest that combining an EGFR TKI with a VEGF pathway inhibitor may enhance clinical activity compared with monotherapy with a first-generation EGFR TKI. The biologic rationale behind this combination is that the EGFR and VEGF signaling pathways are costimulated in EGFR-mutated NSCLC, with upregulated EGFR leading to upregulation of VEGF.20 Increased VEGF signaling promotes angiogenesis and supports oncogenesis, while also contributing to the development of EGFR TKI resistance. Thus, agents inhibiting VEGF signaling can sensitize tumor cells to other anticancer therapies, such as EGFR TKIs.
Approval of the first such combination was based on the results of the registrational RELAY trial, which compared erlotinib plus ramucirumab vs erlotinib plus placebo in participants with previously untreated metastatic NSCLC harboring an EGFR exon 19 deletion or L858R mutation.21 RELAY demonstrated that the combination therapy significantly prolonged the median PFS vs single-agent erlotinib (19.4 months vs 12.4 months, respectively), with a 41% reduction in the risk of progression or death (P <.0001). These results led to the FDA approval of first-line erlotinib plus ramucirumab for patients with metastatic NSCLC and an EGFR exon 19 deletion or L858R mutation.22
Edward B. Garon, MD, MS:
Dr. Piotrowska, would you share your thoughts about the clinical potential for combining an EGFR TKI with a VEGF(R) inhibitor and the potential challenge for uptake of these regimens in clinical practice?
Zofia Piotrowska, MD, MHS:
In the United States, western Europe, and other regions where first‑line osimertinib is approved and readily available, the biggest challenge to integrating combination therapy with an EGFR TKI and VEGF(R) inhibitor is that the established options use a first-generation EGFR TKI (eg, erlotinib). With the third-generation EGFR TKI osimertinib being so effective, well tolerated, and CNS penetrant, as Dr. Le summarized, it is hard to justify treating a patient with earlier-generation EGFR TKIs, even as part of a combination regimen.
The arguments in support of using the combination approach are that, first, the RELAY data show a median PFS for the combination regimen that is comparable to that reported with single-agent osimertinib in the FLAURA trial.18,21 Although cross-trial comparisons indicate a comparable median PFS with osimertinib vs erlotinib plus ramucirumab, the combination regimen has a greater risk of toxicities. Furthermore, the combination approach requires infusion of the VEGF inhibitor and, as a consequence, more frequent trips to the clinic. My perception is that the quality of life for patients treated with first-line combination therapy suffers relative to those who receive first-line osimertinib.
Second, we could argue that using the combination regimen in the first-line setting would allow us to reserve osimertinib for after disease progression. However, I do not recommend sequencing osimertinib because we know that only approximately one half of patients treated with a first-generation EGFR TKI, at best, will develop an EGFR T790M resistance mutation, so not everyone would be guaranteed the benefit of osimertinib using this strategy. Updated RELAY data from Japanese patients showed that just under one half developed the EGFR T790M resistance mutation while being treated with erlotinib plus ramucirumab.23 This analysis used liquid biopsy to detect EGFR T790M and, thus, likely underestimated its prevalence, but we can still infer that a notable proportion of patients will not harbor EGFR T790M at progression on the combination. This limits patients’ treatment options because the EGFR T790M mutation must be present for a patient to be eligible for osimertinib at progression.15
Given those reasons and the availability of osimertinib, I do not recommend combination therapy with a first-generation EGFR TKI plus a VEGF inhibitor. It would be interesting to know whether the combination regimen is preferred in regions where first-generation EGFR TKIs are still used as a first‑line therapy.
Edward B. Garon, MD, MS:
Thank you. Dr. Piotrowska raises an interesting question about regional differences in practice patterns, which we will discuss next.
Edward B. Garon, MD, MS:
Using our survey data, we compared which first-line therapy was used for EGFR-mutated advanced NSCLC by region (US vs Europe vs rest of the world). Among HCPs practicing in the United States and in Europe, approximately three quarters indicated that they most often use osimertinib as a first-line therapy for patients newly diagnosed with EGFR-mutated advanced NSCLC. By comparison, only 27% of HCPs in the rest of the world indicated that they most often use osimertinib, with slightly more than one half indicating that they most often use either a first- or second-generation EGFR TKI.
Table 7. In your practice, what frontline therapy are you using for most of your patients with newly diagnosed EGFR-mutant advanced NSCLC?
Zofia Piotrowska, MD, MHS:
From my discussion with colleagues, my sense is that this reflects an access issue that varies from country to country.
Edward B. Garon, MD, MS:
Yes. Multiple factors could be contributing to the selection of first-line therapy, including osimertinib approval and availability, reimbursement issues, and HCPs possibly reserving osimertinib for progressive disease with an EGFR T790M mutation.
If we look at the comparison by region again, only one quarter of patients with EGFR-mutated advanced NSCLC in the rest of the world are receiving recommended first-line treatment with osimertinib compared with approximately three quarters in the US and Europe. However, combination regimens are not used more often in these regions where first- and second-generation EGFR TKIs are still used. I wonder if this is a reflection of not having OS data from the RELAY trial yet.
Dr. Socinski, what OS benefit would you need to see from RELAY to increase your interest in the combination regimen?
Mark A. Socinski, MD:
For me to consider using erlotinib plus ramucirumab, its OS benefit would have to be substantially better than what was observed for osimertinib in FLAURA, so an HR much lower than 0.80 and a median OS at least 6 months longer, if not more, than the 38.6 months achieved with osimertinib.
Helena A. Yu, MD:
I think exceeding the 38-month OS benefit we see with osimertinib is unlikely to be seen with erlotinib plus ramucirumab. However, it will be interesting to see how our ongoing clinical trials evaluating osimertinib-based combinations—whether with ramucirumab and bevacizumab—play out.
Edward B. Garon, MD, MS:
The next question asked HCPs about their awareness of the relative prognosis of patients with advanced NSCLC being treated with first‑line EGFR TKIs who have EGFR exon 19 deletions vs those who have the L858R mutation.
More than 50% of HCPs indicated that patients with advanced NSCLC and exon 19 deletion do better than those with exon 21 L858R mutations, whereas 13% and 4% reported that patients did similar and worse, respectively. Approximately one third reported they were unsure.
Table 8. Which of the following best describes the relative prognosis of patients with advanced NSCLC being treated with first-line EGFR TKIs who have EGFR exon 19 deletions compared with those who have exon 21 L858R mutations?
Edward B. Garon, MD, MS:
There have been several case series published on differential outcomes for patients with advanced NSCLC and an EGFR exon 19 deletion compared with those with an exon 21 L858R mutation, which in general, has shown a trend toward slightly better outcomes for patients with exon 19 deletions.
Dr. Le, could you please summarize what we know about how these 2 patient subgroups respond to first-line EGFR TKI therapy, along with telling us a bit about what you learned from the mutational landscape analysis of 16,715 patients with EGFR-mutated NSCLC recently published in Nature that you were a coauthor on?24
Xiuning Le, MD, PhD:
In a prespecified subgroup analysis of the FLAURA trial evaluating osimertinib vs erlotinib or gefitinib, a PFS benefit with osimertinib was observed in patients with both EGFR classical mutation types, with an HR of 0.43 for exon 19 deletions and 0.51 for L858R mutations (P <.001 for both). However, the numerical value for median PFS was lower for patients with L858R mutations at 14.4 months (95% CI: 11.1-18.9) compared with 21.4 months (95% CI: 16.5-24.3) for those with exon 19 deletions.18
In contrast, preliminary data from the RELAY trial evaluating the addition of a VEGFR inhibitor to first-generation EGFR TKI therapy showed that the combination of ramucirumab plus erlotinib yielded a comparable improvement in investigator-assessed PFS for patients who harbored an EGFR exon 19 deletion (median PFS: 19.6 months; HR: 0.65) or an L858R mutation (median PFS: 19.4 months; HR: 0.62).21
That said, in the analysis by our group at MD Anderson published in Nature, we actually grouped deletion 19 and L858R mutations, along with a few other similar mutations, into a “classical-like” group. For this analysis, we performed protein structure modeling of mutations in exons 18-21 of the EGFR receptor, which encompass the kinase domain, in an attempt to correlate the structure-function relationship of EGFR mutations with sensitivity to the various generations of available EGFR TKIs.24 Along with the “classical-like” group, we also identified 3 other groups with shared commonalities in their protein structure: EGFR T790M-like mutations, EGFR exon 20 insertions, and a group of atypical mutations, including those in exon 18, which we classified as PACC (P-loop αC-helix compressing) mutations. Thus, despite the numerically worse outcome with osimertinib seen for patients with L858R mutations in FLAURA, it appears that the classical mutations may be more alike compared with the overall landscape of existing EGFR mutations in lung cancer. That said, moving forward, I do think we are going to continue to better define different EGFR mutation groups, and to maximize the benefit to patients, develop drugs specific for each group.
Edward B. Garon, MD, MS:
Thank you, Dr. Le. Dr. Yu, you also have access to a large dataset of patients with EGFR-mutated NSCLC at your institution. What are your thoughts about data showing differential outcomes for patients with EGFR exon 19 deletions vs L858R mutations?
Helena A. Yu, MD:
Although we have consistently seen slightly better outcomes for patients with exon 19 deletions compared with those with L858R mutations across small case series, I tend not to make too much of it. In my practice, I do not treat patients with EGFR L858R differently from those with an exon 19 deletion. However, I agree with Dr. Le that in the future, we may be able to use the type of mutation to better prescribe care for our patients. For example, it is also known that patients with an EGFR L747P mutation have worse outcomes than those with other exon 19 mutations.
Helena A. Yu, MD:
Along those lines, an area ripe for further investigation concerns patients harboring atypical EGFR sensitizing mutations such as those in exon 18, where there is more potential for something other than osimertinib to be beneficial.
Xiuning Le, MD, PhD:
I agree. These make up nearly 15% of all detected EGFR mutations in advanced NSCLC and represent an unmet need.24 Data from our analysis suggest that tumors harboring exon 18 mutations (eg, G719X), and even atypical mutations in exon 20 (eg, S768I), may be more sensitive to second-generation than first- or third-generation EGFR TKIs.
Helena A. Yu, MD:
Indeed, the second-generation EGFR TKI afatinib is uniquely approved for the treatment of advanced NSCLC with an atypical exon 18 mutation G719X, along with S768I in exon 20 and L861Q in exon 21, based on a retrospective analysis.25
Helena A. Yu, MD:
In a pooled post-hoc analysis evaluating afatinib in patients with NSCLC and atypical EGFR mutations from the LUX-Lung 2 (NCT00525148), LUX-Lung 3 (NCT00949650), and LUX-Lung 6 (NCT01121393) clinical trials, investigators reported an overall response rate of 71%, a median duration of response of 11 months, and a disease control rate of 84%.26 Of note, the response rate was 100% in 8 patients whose tumors harbored the exon 20 S768I mutation and 78% in 18 patients with an exon 18 G719X mutation.
Osimertinib has also shown activity in patients with tumors harboring exon 18 G719X (response rate: 53%), exon 20 S768I (38%), and exon 21 L861Q mutations (78%).27
Edward B. Garon, MD, MS:
In addition to the type of EGFR mutation influencing a response to EGFR TKI therapy, as we just discussed, there is also emerging evidence that co-mutations can affect outcomes in patients with EGFR-mutated NSCLC.
Dr. Yu, could you please tell us a bit about your study looking at co-mutations in patients with EGFR-mutated NSCLC?
Helena Yu, MD:
Sure, Dr. Garon. We performed NGS on biopsy tissue from 374 consecutive patients with metastatic EGFR-mutated NSCLC before and after EGFR TKI therapy and correlated the resulting mutation data with their clinical data.28 The most frequent concurrent alterations in 200 pretreatment samples were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Patients who had a TP53 mutation (P = .006), MET amplification (P = .029), or HER2 amplification (P =.018), in addition to their EGFR mutation, exhibited a shorter time to progression on EGFR TKI therapy, as can be seen here for TP53. Our data also showed that having a TP53 mutation is associated with a shorter OS from the start of EGFR TKI therapy (not reached without vs 47 months with; HR: 2.04; P = .03).
Edward B. Garon, MD, MS:
Thank you, Dr. Yu. I am particularly intrigued by the TP53 co-mutation data, which have been recapitulated in other studies.29 We have also now seen analyses where adding an antiangiogenic agent to EGFR TKI therapy is associated with benefit among patients with EGFR-mutated NSCLC who have TP53 co-mutations.21,30 Seen here are results from the RELAY trial, which we discussed above, now showing that adding ramucirumab to erlotinib improved outcomes for patients with TP53 co-mutations, regardless of whether they had an EGFR exon 19 deletion or L858R mutation.
Edward B. Garon, MD, MS:
Dr. Piotrowska, can you comment on whether you see clinical practice evolving toward patients being treated differently based on whether they have an L858R mutation vs an exon 19 deletion, or if they have a TP53 co-mutation? Do you anticipate big changes to our current armamentarium?
Zofia Piotrowska, MD, MHS:
I am not convinced that we are going to be treating patients with EGFR exon 19 deletions differently than L858R mutations, nor those harboring TP53 co-mutations.
There can be notable heterogeneity in patient outcomes even within the population of those harboring exon 19 deletions. For patients with disease harboring common mutations, I do not yet envision a scenario in which we tailor treatment to the specific type of mutation in the same way that we have begun treating the uncommon mutations. That being said, the rate at which these uncommon mutations are being identified and recognized as a unique entity is increasing, as discussed by Dr. Le and Dr. Yu above. I see more referrals from community oncologists saying, “I saw this uncommon mutation, and I do not know what to do with it.” The analysis in Nature that Dr. Le discussed is a start, but ultimately, clinical data will be needed to guide how to treat patients with various uncommon EGFR mutations.
Edward B. Garon, MD, MS:
Thank you, Dr. Piotrowska.
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