EGFR Exon 20 Insertion: A New Player in the NSCLC Landscape

LQ: What kind of unmet needs do you see in the non-small cell lung cancer (NSCLC) field? 
PM: Many NSCLC patients have oncogenic driver mutations in the epidermal growth factor receptor (EGFR) gene, which cause EGFR to constantly mediate signals that drive malignant transformation. Most such mutations are deletions in exon 19 or L858R substitution mutations in exon 21 (see Figure 1). The next most common EGFR mutations are insertions in exon 20. This relatively understudied group is important because they are not only oncogenic but are also difficult to inhibit with currently available EGFR tyrosine kinase inhibitors (TKIs). There’s no good standard of care in such cases; doctors default to older approaches, such as platinum chemotherapy. Consequently, these patients have a median overall survival of ~16 months, compared with ~40 months for patients with exondefault to older approaches, such as platinum chemotherapy. Consequently, these patients have a median overall survival of ~16 months, compared with ~40 months for patients with exon 19 deletions or L858R substitutions. In brief, patients with exon 20 insertions aren’t benefiting from personalized therapies – and that’s a serious unmet need.

LQ: Janssen is addressing this unmet need with the breakthrough product, amivantamab (1). Amivantamab was approved in May 2021 by the US FDA for treatment of EGFR exon 20 insertion NSCLC that progressed on prior platinum-based chemotherapy. For this underserved group of patients in the NSCLC community, its approval could have a huge impact – no longer will they feel like EGFR outcasts! And now, focusing on mutations, can you help us understand the difference between TKI resistance-associated EGFR mutations, such as T790M, and exon 20 insertions?

PM: The difference is that exon 20 insertions, like exon 19 deletions and L858R substitutions, are driver mutations. Resistance mutations, by contrast, occur later in tumor evolution, when the selective pressure of TKI therapy favors outgrowth of resistant clones – only tumor cells with resistance mutations can survive and proliferate in a TKI environment. So it’s important to test for those types of genetic changes, including T790M, which is one of the most common resistance mutations to first- and second-generation TKIs. More recently, with osimertinib, a third-generation TKI, being used, new resistance patterns such as C797S and MET amplifications are common.

LQ: How should we test for these changes? What is your view on single-marker tests versus multiplex panels?PM: There are many mutations of interest – not just in EGFR but also in, for example, KRAS and ALK. Full genomic testing, as early as possible, is essential if we are to rationally choose optimal therapy. It makes sense, therefore, to opt for next-generation sequencing (NGS), which can detect all relevant genetic changes. Some use real-time PCR, but our analysis (2) showed that PCR detects only about 50 percent of the exon 20 insertion mutations found by NGS. We believe that is largely why exon 20 insertion mutations are currently underdiagnosed – people are using the wrong detection technology. In fact, even NGS tests can miss these mutations if the tests are improperly calibrated – you have to set them up carefully to ensure that they can detect all the different variant types. So, in addition to having the right technology, you need the right education regarding heterogeneity and presentation of exon 20 insertions. This is essential – misdiagnosis of patients can have farreaching consequences. And remember that all patients on TKI therapy will eventually progress and require additional tests to assess resistance mutations. Biopsies from tumor tissue are best in these cases, because they permit higher sensitivity, but if that’s not an option – for example, where the tumor mass is inaccessible – we can test circulating tumor DNA. But here again it is difficult to justify using any approach other than NGS.

LQ: So to avoid the issue of underdetecting exon 20 insertion mutations, it is critical to choose the right kind of test – and, in this context, NGS is clearly superior to PCR. Does NGS have any disadvantages?
PM: NGS turnaround times could be a drawback (although, for clarity, not all NGS tests have comparable turnaround times, so choosing wisely is again critical). Many NSCLC cases are diagnosed only after the cancer has metastasized; these highly symptomatic patients need to start therapy immediately, which means they need test results immediately. Unfortunately, many patients wait too long for their NGS results and must revert to the standard of care for people with unknown driver mutations – namely, platinum-based chemotherapy and immunotherapy. Consequently, when the NGS results finally come through, these patients must either finish the platinum course – which means delaying the EGFR therapy that will target their specific cancer – or switch to another therapy with different side effects. That’s not the best way to manage patients; it’s far better to have the NGS test results upfront.

LQ: What needs to be done to improve the situation?
PM: Education is needed to inform the NSCLC community about our new therapy (1) and how it addresses unmet needs. One barrier to amivantamab adoption is the idea that EGFR treatments have been around for years, so another EGFR therapy won’t be any different. That’s why we have to make clear that this new therapy targets a very specific group of patients who don’t respond to standard EGFR therapies.

LQ: Yes, it is important for doctors to understand the different EGFR mutations and appreciate the importance of using the right test at the right time to ensure that patients with exon 20 insertions are never again left behind. But we should also remember that this drug is at the beginning of a journey; real-world clinical data will be of paramount importance, as there may be issues that aren’t apparent in the context of a controlled clinical trial.

PM: The potential for better treatment is enormous. Not long ago, the idea of personalized medicine was just a dream. Today, we can define the genomic basis of a patient’s progression and treat them accordingly. It’s so impressive to see great responses to treatments that have been prescribed on the basis of genetic tests. And then, for those patients who progress, to see them switch to a different drug and respond to that treatment. By tracking each cancer’s evolution and treating it with precision therapy, we are impacting many lives and helping patients to survive longer than ever before.

Thermo Fisher Scientific and Janssen Oncology have an agreement to validate the Oncomine Dx Target Test for multiple biomarkers as CDx claims in NSCLC and additional oncology indications. Earlier in 2021, Thermo Fisher Scientific filed for FDA approval of the test as CDx to identify NSCLC patients with EGFR exon20 insertions who are candidates for amivantamab.

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