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:
We have already discussed some possible new directions in the management of EGFR-mutated NSCLC, including further dissecting our treatment choice based on the type of EGFR mutation or the presence of a co-mutation. We will turn now to a discussion of key clinical trials in the settings of first-line and progressive disease.
Our survey asked HCPs how often they consider clinical trials for patients newly diagnosed with advanced EGFR mutation–positive NSCLC. Of the 76 HCPs who answered this question, 44% indicated they always or often considered a clinical trial, with another 22% indicating they sometimes do. Of the remaining 24%, 22% rarely considered a clinical trial for these patients and 12% never did.
Table 9. How often do you consider clinical trials for your patients with newly diagnosed advanced EGFR mutation–positive NSCLC?
In the setting of progressive disease, 55% of responding HCPs indicated they always or often consider a clinical trial, which is an 11% increase from what we just saw for newly diagnosed disease. Sometimes considering a clinical trial was chosen by 16% of responding HCPs, rarely by 17%, and again, 12% indicated they never considered a second-line clinical trial for these patients.
Table 10. How often do you consider clinical trials for your patients with advanced EGFR mutation–positive NSCLC after progression on frontline EGFR TKI therapy?
For this discussion, I would like each of you to share 1 trial you are excited about and why.
Edward B. Garon, MD, MS:
Dr. Socinski, could you describe a trial in the first‑line setting that you think has the potential to improve upon our first-line SoC osimertinib?
Mark A. Socinski, MD:
Most recently, I enrolled a patient on the FLAURA2 trial evaluating the combination of osimertinib plus platinum-doublet chemotherapy in the first‑line setting.
The randomized phase III FLAURA2 trial was motivated by 2 phase II trials that showed both PFS and OS benefit with gefitinib plus chemotherapy vs chemotherapy alone in EGFR-mutated NSCLC.48,49 However, as you mentioned, osimertinib has since become the SoC treatment in the US and other regions, so FLAURA2 was designed to answer the same question—will the addition of chemotherapy to EGFR TKI therapy improve outcomes in patients with newly diagnosed EGFR-mutated NSCLC?—but now with osimertinib. In FLAURA2, patients were randomized to osimertinib plus platinum-based chemotherapy followed by osimertinib maintenance with or without pemetrexed every 3 weeks or osimertinib alone until disease progression or unacceptable toxicity. The primary endpoint was PFS by blinded independent central review per RECIST V1.1.
My patient was randomized to the triplet arm of osimertinib plus platinum-doublet chemotherapy. She had a fantastic response and is now on maintenance osimertinib and pemetrexed.
Edward B. Garon, MD, MS:
Thank you, Dr. Socinski. It will be interesting to see if adding 4 cycles of platinum-doublet chemotherapy to osimertinib improves survival for these patients, as was seen in the phase II studies with gefitinib.
Zofia Piotrowska, MD, MHS:
I will note a similar first-line study to FLAURA2, with Dr. Yu as the principal investigator. The distinguishing feature of this randomized phase II study is that patients are screened for the clearance of EGFR-mutant circulating tumor DNA (ctDNA) before randomization (NCT04410796). Presence of EGFR-mutant ctDNA has been shown to be a predictive marker of suboptimal response to osimertinib monotherapy.50 Thus, in Dr. Yu’s trial, only patients with detectable EGFR-mutant ctDNA after 2 cycles of osimertinib treatment are randomized to receive either osimertinib alone or in combination with platinum-doublet chemotherapy. The patients who clear EGFR-mutant ctDNA go off trial. The primary endpoint is PFS at 2 years.
I think osimertinib plus chemotherapy has potential, but considering the toxicities incurred with adding chemotherapy to a very well-tolerated drug, I hope that in the future we will be able to select the patients who actually need that combination rather than overtreating those who might do well with osimertinib alone.
Edward B. Garon, MD, MS:
Good point, thank you, Dr. Piotrowska.
Edward B. Garon, MD, MS:
We will move on now to investigations in progressive disease. Dr. Le, what are your thoughts on clinical trials in this setting?
Xiuning Le, MD, PhD:
Clinical trials of agents targeting mechanisms of resistance to osimertinib are important for our patients. As we discussed above, we are gaining a better understanding of the molecular bypass pathways that lead to osimertinib resistance, and thereby identifying potential targets for second-line therapy.33 After osimertinib failure, I recommend complete molecular testing by NGS to try to identify the mechanism of resistance, and if found, enrollment in an applicable clinical trial, if possible, or use of off-label targeted therapies in particular instances, as we discussed above.
I still enroll patients in the phase II ORCHARD trial, which is a platform study that matches patients with EGFR-mutated advanced NSCLC progressing on first-line osimertinib to a targeted therapy based on molecular characterization of their tumor.37 There are arms for MET alterations, the on-target EGFR C797X mutation, other EGFR alterations, and ALK or RET rearrangements, among others. Continuing a patient on an all-oral regimen targeting a specific identified bypass pathway has significant value for patients, including psychologically.
Edward B. Garon, MD, MS:
Thank you, Dr. Le.
Edward B. Garon, MD, MS:
Dr. Yu, is there a particular trial that you are excited about in patients who have progressed on first-line osimertinib or in those without an EGFR T790M mutation who progressed on an earlier-generation EGFR TKI?
Helena A. Yu, MD:
I first want to point out that standard platinum-based doublet chemotherapy works well and is tolerated in the second-line setting for EGFR-mutated NSCLC, so for community oncologists, I recommend this regimen. However, after second-line platinum-doublet chemotherapy, the standard options are docetaxel or gemcitabine, which are each quite disappointing in terms of efficacy, and this is when I urge community clinicians to refer patients for clinical trials.
In this disease setting, I am most excited about the HER3-directed antibody–drug conjugate patritumab deruxtecan. A phase I dose-escalation and expansion trial (NCT03260491), which is still recruiting, reported an ORR of 39% and a PFS of 8.2 months with patritumab deruxtecan in 44 patients with advanced or metastatic EGFR-mutated NSCLC with previous EGFR TKI and platinum-doublet chemotherapy exposure, including responses in patients with known and unknown EGFR TKI resistance mechanisms.52 These are encouraging results in a challenging setting after both an EGFR TKI and chemotherapy.
Edward B. Garon, MD, MS:
Thank you, Dr. Yu.
Edward B. Garon, MD, MS:
How about you, Dr. Piotrowska? What trial are you most excited about in the setting of progressive disease?
Zofia Piotrowska, MD, MHS:
An investigational combination regimen that I would highlight is amivantamab and lazertinib. Amivantamab is a bispecific antibody to EGFR and MET with a novel mechanism of action that should bypass TKI resistance.53 As we will discuss next in the last section, this agent has received accelerated approval for the treatment of advanced NSCLC with an EGFR exon 20 insertion on or after platinum-based chemotherapy, which was based on a cohort of the phase I CHRYSALIS trial.54 Lazertinib is a third-generation EGFR TKI with a slightly different structure than osimertinib that also has activity in EGFR-mutated NSCLC.31,55
CHRYSALIS, an open-label phase I multicohort dose-escalation/dose-expansion trial evaluating this combination regimen, included a cohort of patients with metastatic or unresectable EGFR-mutated NSCLC with progression on osimertinib.56 Initial results from 45 patients with disease progression on osimertinib without intervening chemotherapy included an ORR of 36% with a median duration of response not reached after a median follow-up of 11.0 months.
We also have recent data for this combination regimen from the 2022 World Conference on Lung Cancer in patients with EGFR-mutated NSCLC with progression after osimertinib and chemotherapy, which is the setting we just discussed for patritumab above. In the phase I multicohort dose-escalation/dose-expansion CHRYSALIS-2 trial, the cohort of patients who received osimertinib and platinum-doublet chemotherapy (n = 162), whether in sequence, out of sequence, after a first-generation EGFR TKI, or in heavily pretreated patients, demonstrated an ORR of 33% and a median duration of response of 9.6 months with a median follow-up of 10 months.57
In both trials, the safety profile with the combination of amivantamab plus lazertinib was manageable.
These early results are promising, and we are starting to see data hinting that there may be biomarkers of response in patients with resistance mediated through EGFR and MET.56 I would certainly consider the CHRYSALIS-2 trial (NCT04077463), which is still recruiting, for patients after progression on osimertinib and chemotherapy.
I agree with Dr. Yu that novel therapies like patritumab deruxtecan or the novel combination amivantamab plus lazertinib are currently most important for patients who maintain a good functional status in the later-line settings in which we do not have good treatment options. That said, seeing good activity with a novel therapy in later‑line settings may also create opportunities to evaluate these agents in earlier stages of disease, which is already happening with amivantamab. For example, the ongoing phase III MARIPOSA trial is assessing amivantamab plus lazertinib as first-line therapy (NCT04487080) and the phase III MARIPOSA-2 trial is evaluating amivantamab plus lazertinib plus carboplatin plus pemetrexed following progression on osimertinib (NCT04988295).
Edward B. Garon, MD, MS:
Thank you, Dr. Piotrowska.
Edward B. Garon, MD, MS:
Another promising investigational agent in the setting of progressive disease is the TROP2-directed antibody–drug conjugate datopotamab deruxtecan, which was evaluated in a cohort of patients with advanced or metastatic NSCLC in the phase I TROPION-PanTumor 01.58 Approximately 15% of patients in this cohort had EGFR mutations. Datopotamab deruxtecan was associated with durable antitumor activity in this cohort, with an ORR ranging from 24% to 28% across different doses, and a manageable safety profile. TROPION-PanTumor is still recruiting (NCT03401385), and this agent is now being investigated in the phase III TROPION-Lung01 trial (NCT04656652).
To close our discussion of future directions and ongoing trials, I will say that the most interesting thing I have taken away from this discussion is how much things have changed over time. In the era of targeted therapy and precision medicine, I never would have thought I would hear my colleagues be excited about chemotherapy again. Faced with such evolution, I often explain to my patients that we oncologists are excited about treatments that are effective, even if they are not areas of tremendous conceptual excitement. In the end, we want our patients to do better and I think these are some examples of how that is happening in the settings of newly diagnosed and progressive EGFR-mutated NSCLC.
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