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:
Our last survey question asked, “Are you currently testing for EGFR exon 20 insertion mutations in your patients with advanced NSCLC?” Over three quarters of responding HCPs reported they were testing for EGFR exon 20 insertions, whereas 17% indicated they were not testing for this mutation. Approximately 6% reported being unsure.
Table 11. Are you currently testing for EGFR exon 20 insertion mutations in your patients with advanced NSCLC?
We recognize that testing for EGFR exon 20 insertion mutations is important and routine at most academic centers as part of NGS panels, but many clinicians may not be entirely clear on what their NGS panel includes in terms of this set of mutations. Testing has increased since the FDA issued accelerated approvals for amivantamab and mobocertinib, which are both indicated for the treatment of adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy.54,59
Edward B. Garon, MD, MS:
Dr. Piotrowska, would you please share your perspective on the data behind the approval of amivantamab for patients with EGFR exon 20 insertion–positive advanced NSCLC?
Zofia Piotrowska, MD, MHS:
Of course. As I mentioned, amivantamab is a fully humanized, bispecific antibody targeting EGFR mutations and MET mutations/amplifications, with a mechanism of action including receptor degradation, immune cell–directing activity, and inhibition of ligand binding.53 The accelerated approval was based on the results from the phase I dose-escalation/dose-expansion CHRYSALIS trial that we discussed briefly earlier. This trial also included a cohort of patients with unresectable/metastatic EGFR exon 20 insertion–positive advanced NSCLC with progression on previous platinum-based chemotherapy who received single-agent amivantamab.54,60 Amivantamab initially requires 2 consecutive infusion days, is then given weekly for the first 4 weeks, followed by every 2 weeks starting at Week 5.
In the efficacy population (n = 81), the ORR was 40% and responses were durable, with a median duration of response of 11.1 months. Overall, promising efficacy was seen regardless of the location of insertion in exon 20.
Zofia Piotrowska, MD, MHS:
The safety profile of amivantamab was manageable.54,60 Amivantamab is an infusion‑based therapy and infusion-related reactions were quite common, occurring in 66% of patients. Infusion-related reactions most frequently occurred with the first infusion, but split dosing of the first infusion can mitigate this. Furthermore, patients who have doses withheld due to infusion-related reactions can later resume therapy without any difficulty.
Skin toxicities were also common with this agent, with any-grade rash occurring in 86% of patients, paronychia in 45%, stomatitis in 21%, and pruritus in 17%.
Even though it is not as effective as osimertinib is against the common EGFR mutations, I consider amivantamab to be an effective therapy for patients with an EGFR exon 20 insertion mutation. Also, as the first drug approved in this space, it is certainly a step forward for this patient population in which, for years, we were able to identify them but did not have any good treatment options.
Edward B. Garon, MD, MS:
Thank you, Dr. Piotrowska. My institution also participated in the CHRYSALIS trial, and we were able to manage the infusion-related reactions that you described. However, the first patient I gave it to as the SoC opted to discontinue the drug. Even so, I anticipate that infusion-related reactions would be readily manageable by community HCPs who are already familiar with other agents (eg, rituximab) that can cause infusion-related reactions.
Edward B. Garon, MD, MS:
Dr. Le, would you please share your thoughts on the data behind the approval for mobocertinib for patients with EGFR exon 20 insertion–positive advanced NSCLC?
Xiuning Le, MD, PhD:
Mobocertinib is a first-in-class, irreversible EGFR TKI that targets EGFR exon 20 insertion mutations.59,61 From our EGFR mutation structural analyses that were discussed above,24 we have good preclinical evidence that mobocertinib fits better than osimertinib in the ATP binding pocket, which is smaller in exon 20 insertion–mutated EGFR than in EGFR with a classical mutation. Mobocertinib has a notable difference from amivantamab in that it is an oral EGFR TKI.
Its accelerated approval was based on results from a phase I/II dose-escalation/expansion trial of patients with NSCLC and EGFR exon 20 insertion mutations who previously had received and/or progressed on platinum-based chemotherapy.59,61 In the cohort of platinum-pretreated patients (PPP; n =114), the confirmed ORR by independent central review was 28%, with a median duration of response of 17.5 months and a median PFS of 7.3 months.
Xiuning Le, MD, PhD:
Mobocertinib has a black box warning for QTc prolongation and Torsades de Pointes, and patients receiving this drug need to be carefully monitored at baseline and during treatment.59 Treatment with mobocertinib is also associated with diarrhea and rash at 91% and 45% of patients in the PPP cohort, respectively—2 common on-target EGFR toxicities.61 Other common any-grade adverse events include paronychia, a decreased appetite, and nausea (38%, 35%, and 34%, respectively, in the PPP cohort).
Edward B. Garon, MD, MS:
Thank you both. We are very fortunate to now have 2 targeted therapies approved for patients with EGFR exon 20 insertion–positive advanced NSCLC. A follow-up question for Dr. Piotrowska and Dr. Le: How are you using these agents in your clinical practice?
Zofia Piotrowska, MD, MHS:
It is important to first note that neither amivantamab nor mobocertinib is currently approved as a first-line treatment for EGFR exon 20 insertion–positive advanced NSCLC. 54,59 For a newly diagnosed patient, neither of these therapies would be a first‑line treatment option outside of a clinical trial. Instead, the SoC for these patients is to lead with platinum-doublet chemotherapy in the frontline setting.
Xiuning Le, MD, PhD:
In my clinic, I discuss both agents when a patient progresses during or after platinum-based chemotherapy—the setting that Dr. Piotrowska just mentioned. The routes of administration, dosing schedule, and associated adverse events are very different between the 2 agents and may make a difference to an individual patient. I often encounter a patient who already knows the one they want to try, but if the patient defers to me, then I look to the response data available for each agent. Numerically speaking, amivantamab is modestly better. Furthermore, I think that amivantamab is probably a little easier to tolerate, outside of the logistical issue of having to come to the infusion center.
That said, the conversation is really around sequential use, as I would expect the mechanisms of resistance to differ for these agents because amivantamab is antibody based, whereas mobocertinib is a TKI. In fact, we have evidence supporting this with another investigational EGFR exon 20 insertion inhibitor, poziotinib, in the setting of HER2 exon 20–mutated NSCLC. In a phase II study, patients who had previous antibody–drug conjugate therapy or another antibody‑based drug before receiving poziotinib had a similar likelihood of response with poziotinib compared with those who were not pretreated with an antibody-based drug.62 This supports that a patient may be able to receive both amivantamab and mobocertinib at different times in the course of their treatment.
Edward B. Garon, MD, MS:
Thank you, both. Dr. Socinski, what are your thoughts on the sequencing of these new agents?
Mark A. Socinski, MD:
I completely agree with my colleagues’ comments that we should be using these agents sequentially in our patients with EGFR exon 20 insertion–positive advanced NSCLC after progression on chemotherapy, with the caveat that the order may be bound by clinical pathways, as is the case at my institution. In this scenario, amivantamab was approved first and added to the clinical pathway as the treatment of choice following platinum-based chemotherapy for these patients. Then, along came the approval of mobocertinib and the committee who makes these decisions, which I am on, posed a few questions: Is the efficacy of mobocertinib better than amivantamab? The answer was no. Is it less toxic? The answer was no. The third consideration is cost, which we do not have an answer for yet. As a result, the clinical pathway still lists amivantamab as the drug to follow chemotherapy, but we did add an out that says mobocertinib can be used instead of amivantamab if the patient desires an oral therapy.
Edward B. Garon, MD, MS:
Good point, thank you, Dr. Socinski.
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