Biomarker testing is part of the management of all patients with metastatic non-small cell lung cancer and actually also some patients without metastasis but maybe this is not the topic for our discussion today. In a patient with non-squamous cell carcinoma, metastatic, the reflex testing includes PD-L1, which is an immunohistochemistry and this may drive the decision making for immunotherapy. On the other hand you need to do NGS, meaning next generation sequencing, looking at multiple genes for oncogenic alterations. NGS may be done on DNA for mutations or on RNA to detect gene rearrangements. We have four alterations for which we have targeted therapies approved in the first-line setting and part of the ESMO Clinical Practice Guidelines recommendations – EGFR mutations, ALK gene rearrangements, ROS1 rearrangements and BRAF mutations. But obviously there are other subgroups of patients. These alterations are mutually exclusive one from another and beyond those four alterations, for which we have treatment based on a targeted agent in the first-line setting, we have multiple other alterations for which we do have some targeted agents but right now approved or available from second line, so meaning those patients will be receiving platinum-based chemotherapy, possibly with immunotherapy, and then you will have to go back to the NGS report and see whether there is an oncogenic alteration leading to an opportunity for targeted treatment. 

This is true for KRAS. We just saw at the plenary session of the ESMO 2022 meeting the results from the CodeBreaK trial with sotorasib, which is a targeted agent against KRASG12C mutations, that was compared to docetaxel. So KRAS is a typical example of an alteration amenable to a targeted treatment, as of today, in the second-line setting. We have other alterations – we have MET, we have RET, we have NTRK and we have some uncommon EGFR mutations such as exon 20 insertion mutations which are observed in about 3-4% of patients with non-squamous cell carcinomas.

Would you like to share any real world data that shows the importance of identifying exon 20 mutations?

Those patients have an aggressive disease and this is what we see from the CATERPILLAR study just presented at this ESMO ‘22 meeting. We have also data from Japan through the LC-SCRUM network. What we can see in the second-line setting and beyond those patients with EGFR exon 20 insertion mutations, they do have aggressive disease with multiple metastases, rapidly progressing disease and the PFS in a real world setting ranges from 3-4 months. So this is not that much and the overall survival of patients, again, is limited, less than one year for the majority of those patients. This is because we miss access historically to dedicated treatment for those patients with exon 20 insertions.

So what was presented during this meeting is very interesting because these are indirect comparisons between a clinical trial that assessed amivantamab, a dual specific EGFR-MET antibody, that has shown some efficacy in phase I/II studies for those patients with exon 20 insertions, and those real world data generated before the availability of amivantamab. So a really interesting approach to try to match patients, similar to what we do in a randomised study, but here it’s called indirect because we are comparing results from a clinical trial, phase I/II study, the CHRYSALIS study which assessed amivantamab, to those historical cohorts but through a matching of patients, matching of the characteristics of the patients – gender, age, location of metastasis, these kinds of characteristics.

What are the results on this comparison?

It’s really interesting to see that in those comparisons we can see that the response rate with amivantamab is two times, three times higher than that of historical treatment such as chemotherapy, such as docetaxel or other single agent chemotherapy. And with amivantamab we have a reduction by 50% or more of the risk of death and disease progression. So clearly it’s not a randomised study but it’s a way to assess the magnitude of benefit with amivantamab as compared to other controls, an experimental control arm.

Could you comment on the European real-world study regarding the treatment of exon20ins NSCLC with amivantamab?

What is striking in those posters presented during the meeting is that from the Japanese study, from the European studies, the CATERPILLAR study, from other comparisons in a larger Asian population, we have a similar result. The hazard ratio for response rate, for PFS and OS in those indirect comparisons are all the same, at least in the same range. So it shows that we have a consistent benefit observed with amivantamab as compared to historical treatment.

This is a moving field we have, beyond amivantamab, TKIs such as mobocertinib or sunvozertinib, these showing efficacy in the setting of EGFR exon 20 insertion mutations. We have a discussion about the sequencing of treatment – should these drugs move to the first-line setting, which would be logical given their efficacy in the late-line setting? There are ongoing trials, such as the PAPILLON trial, combining chemotherapy plus amivantamab versus chemotherapy alone in those patients with EGFR exon 20 insertions. What does that mean? It means that information about the EGFR status will be required, also for those uncommon mutations from the decision-making for first line in all the patients.

Could you comment on the tolerability of these results?

That’s a very good point because obviously we have the efficacy but we have also to consider the side effects. These drugs are associated with side effects related to the EGFR inhibition, meaning gastrointestinal tract related side effects, cutaneous side effects such as rash and, for amivantamab, infusion related reactions. The more patients we are treating, the easier it is to manage and prevent in a proactive manner those side effects. 

It’s very important to build a multidisciplinary management of those patients. At my institution, Institut Curie, we have a dedicated nurse to monitor the cutaneous toxicities of amivantamab and other drugs associated with such side effects. It’s very important for the patients; it’s really helpful to keep the toxicities with grade 1, not leading to grade 2 or 4 which would mean a discontinuation of the drug. So that’s very interesting management because being proactive means also educating the patients about those side effects so that the patient has a quick reaction when something appears. These treatments are associated with a long-term benefit, meaning a long duration of treatment. So it’s very important to ensure that tolerability is okay for the patients.