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Assistant Professor of Medicine
Division of Thoracic Medical Oncology
Department of Medical Oncology
NYU Langone Health Perlmutter Cancer Center
Attending Physician, Thoracic Medical Oncology
Department of Medicine
Perlmutter Cancer Center
NYU Langone Health
New York, New York
Joshua Sabari, MD, has disclosed that he has received consulting fees from AstraZeneca, Genentech, Janssen, Navire, PharmaMar, Regeneron, Sanofi Genzyme, and Takeda.
Approximately 20% to 25% of patients with advanced non-small-cell lung cancer (NSCLC) we see in clinical practice have and actionable mutations in the EGFR gene, mostly comprising exon 19 deletions and exon 21 mutations. The third most common type of EGFR mutation are the exon 20 insertion (ex20ins) mutations, seen in approximately 4% to 12% of patients with EGFR-mutated disease. Of importance, patients with EGFR ex20ins mutation–positive advanced NSCLC often do not respond to standard EGFR tyrosine kinase inhibitors (TKIs), like osimertinib, and the standard of care for this group of patients remains limited to platinum-based doublet chemotherapy in the frontline setting. The role of immunotherapy in this setting is controversial and associated with the potential increased risk of immune-related toxicities if subsequent EGFR TKI treatment is given. Until very recently, we have not had successful therapies targeting this alteration.
Early data from the ECOG-ACRIN 5162 trial showed an ORR of 25% in patients (N = 21) with EGFR ex20ins mutations who were treated with twice the standard dose of osimertinib (160 mg), data that were recently corroborated by a study presented at the 2021 European Society of Medical Oncology meeting. But in my opinion, this will not be an effective strategy for moving the care of these patients forward. We need novel therapeutics specifically targeting the EGFR ex20ins.
One such agent is poziotinib, an investigational selective, irreversible inhibitor of both EGFR and HER2 with ex20ins mutations. In 2018, a phase II study with poziotinib showed an ORR of 55% and a progression-free survival of 5.5 months in heavily pretreated patients with EGFR ex20ins mutation–positive NSCLC. Unfortunately, later results did not substantiate these initial findings. Subsequent response rates decreased, mostly due to toxicities such as rash and diarrhea resulting from inhibition of wild‑type EGFR. However, data from the phase II ZENITH20 trial presented at the 2021 American Association for Cancer Research meeting evaluating poziotinib with an 8-mg twice-daily dosing strategy (vs the original approach of 16 mg once daily) showed an improved safety profile. High-grade adverse events were reduced by nearly one third, dose interruptions were halved, and preliminary data suggest enhanced efficacy. Additional data of 16-mg once-daily poziotinib from this trial presented at the 2021 American Society of Clinical Oncology (ASCO) meeting showed promising central nervous system (CNS) activity with a 22% ORR in this patient population. Future studies will likely continue with twice-daily dosing regimens, but currently, the utility of poziotinib is limited by the high toxicity rate that can be difficult to mitigate and manage in the clinic.
Newly Approved Therapies for Advanced NSCLC With EGFR ex20ins Mutations
Amivantamab is a bispecific EGFR and c‑Met antibody that recently obtained accelerated approval by the FDA for adults with locally advanced or metastatic NSCLC with EGFR ex20ins mutations that has progressed on or after platinum-based chemotherapy. This approval was supported by data from the phase I CHRYSALIS multicohort trial that my colleagues and I presented at the 2020 World Conference on Lung Cancer (WCLC) meeting. In the expansion cohort with patients with EGFR ex20ins mutations who were previously treated with a platinum-based doublet, amivantamab was given at the recommended phase II dose of 1050 mg in patients weighing <80 kg and 1400 mg in patients weighing ≥80 kg. Results showed a remarkable ORR of approximately 40%, a median progression‑free survival of 8.3 months, and a duration of response of approximately 11 months.
Amivantamab has a generally tolerable adverse event profile. As an antibody, it can cause infusion reactions particularly during the initial administration. This can be mitigated by splitting the dose over 2 days and pretreating patients with corticosteroids, acetaminophen, and diphenhydramine. The rate of infusion reactions with subsequent doses is quite low (<1%) and very manageable. Of note, adverse events common to small-molecule EGFR TKIs such as rash and diarrhea due to the inhibition of wild-type EGFR are not commonly seen with amivantamab.
Although amivantamab monotherapy is promising, future directions are looking at combination regimens. The PAPILLON study (NCT04538664) is an international, randomized phase III study evaluating amivantamab in combination with chemotherapy vs chemotherapy alone in patients with newly diagnosed locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations. Preliminary data from the CHRYSALIS chemotherapy combination cohort are promising, showing antitumor activity in 4 treatment-naive patients with advanced NSCLC and EGFR ex20ins mutations. Amivantamab is also being studied in combination with lazertinib, a third-generation EGFR TKI, in a different cohort of the CHRYSALIS trial that showed early evidence of durable responses in chemotherapy-naive patients with advanced EGFR-mutated NSCLC and progression on osimertinib. The combination of amivantamab and lazertinib is also being studied vs osimertinib or lazertinib alone as first-line therapy in the phase III MARIPOSA trial (NCT04487080), which is enrolling patients with advanced NSCLC and EGFR exon 19 deletion or exon 21 L858R mutations.
Mobocertinib is a small-molecule TKI active against both EGFR and HER2 ex20ins mutations. Mobocertinib recently received accelerated approval by the FDA for adults with locally advanced or metastatic NSCLC with EGFR ex20ins mutations that has progressed on or after platinum-based chemotherapy. Similar to poziotinib, initial phase I data showed high response rates (ORR: 43%) but later studies revealed more modest, although still good, activity (ORR: 26%). More recent data presented at WCLC 2021 from patients with pretreated disease further corroborated previous findings (ORR: 23%; median progression-free survival: 7.3 months). The safety profile is consistent with that seen for previous EGFR-targeted TKIs, with diarrhea and rash being the most common events (any grade: 92% and 78%, respectively). Other common adverse events include stomatitis, vomiting, and musculoskeletal pain, possibly due to its activity against wild-type HER2. Mobocertinib has a black box warning for QTc prolongation and torsade de pointes.
In just the past few months, we have gone from having no agents specifically targeting EGFR ex20ins mutation–positive advanced NSCLC to 2 options, both indicated in the setting of previously treated disease. Selecting between these 2 agents will be a multifactorial consideration. The first factor is route and frequency of administration. Is the patient comfortable taking a less frequent intravenous infusion or a once-daily oral pill? Which route will result in greater adherence? Another consideration is toxicity. What is the patient’s risk tolerance? What adverse event profile and monitoring schedule is the patient most comfortable with?
Amivantamab has a risk of an infusion reaction with the first dose, but we can mitigate that risk with a standard pretreatment regimen. Also, adverse events related to wild-type EGFR inhibition, such as rash and diarrhea, are very low. With mobocertinib, there is obviously no infusion reaction risk, but grade 3 diarrhea and rash can be significant and disruptive to patient’s health and quality of life potentially leading to dose reduction and eventual discontinuation, thereby limiting efficacy.
Another factor, of course, is efficacy. The response rates for these 2 agents are very different, with amivantamab yielding a higher response rate; however, we cannot make a direct comparison. We can look at the inclusion/exclusion criteria for the trials and use those as an indirect guidance to assess where our patients may have a better chance at having a response.
Finally, a shared decision-making process with our patients should be employed when choosing between these 2 approved therapies. All the factors mentioned above will eventually come down to what the patient wants to do after having an informed conversation with their provider.
Other Emerging Agents Targeting EGFR ex20ins Mutations
There are additional therapies targeting EGFR ex20ins mutations in development. The first is CLN-081, a novel oral EGFR inhibitor with a pyrrolopyrimidine scaffold and broad activity against a variety of EGFR mutations that showed good CNS penetration in preclinical studies. This is an important nuance since patients with EGFR ex20ins mutation–positive advanced NSCLC tend to have higher rates of CNS metastases like we have seen with the more common EGFR mutations. CLN-081 is also more specific to EGFR ex20ins mutations and has limited interaction with wild-type EGFR, thereby reducing associated toxicity compared with some of the earlier targeted therapies used to treat EGFR ex20ins mutation–positive disease. Clinical data presented at ASCO 2021 reported partial response rates of approximately 40% in patients previously treated with platinum-based chemotherapy. It would be especially interesting to see this agent combined with a bispecific antibody such as amivantamab for CNS coverage, multimodal activity, and response durability.
Another novel oral, selective, irreversible inhibitor targeting EGFR and HER2 mutations, including ex20ins, is DZD9008. Promising preclinical and clinical data have been presented at ASCO 2021 and WCLC 2021 (confirmed ORR: 37.5%) in heavily pretreated patients, including those with brain metastases. DZD9008 will likely have a lot of utility not only as a single agent, potentially in later lines of therapy, but also in combination strategies.
Finally, BDTX‑189 is another inhibitor targeting EGFR and HER2 ex20ins mutations for patients with previously treated disease with very preliminary data showing lower response rates, although work is ongoing to define an optimal dose for this agent.
This is a very dynamic era for our patients living with EGFR ex20ins–mutated advanced NSCLC, and I am excited to have 2 new targeted agents in our armamentarium.
Have you incorporated amivantamab and/or mobocertinib into your clinical practice now that they are approved? Do you have any questions on the use of these new agents in clinical practice? Let us know in the comments.