Novel Combinations Challenge Osimertinib Alone in EGFRm Lung Cancer

Jonathan W. Riess, MD

While the standard-of-care recommendations can vary depending on the individual patient, EGFR tyrosine kinase inhibitors (TKIs) like osimertinib (Tagrisso) have played a pivotal role in the treatment of patients with EGFR-mutated lung cancer in recent years.

Osimertinib tends to be the preferred first-line treatment for most patients who harbor common EGFR mutations, including exon 19 deletions or L858R. When evaluated in the FLAURA study (NCT02296125), osimertinib led to superior efficacy and longer progression-free survival (PFS) rates when directly compared with older EGFR TKIs like gefitinib (Iressa) or erlotinib (Tarceva).

However, several drug combinations have shown promise in this space and can potentially improve patient outcomes compared with osimertinib alone. These studies include the phase 3 FLAURA2 trial (NCT04035486) of osimertinib with chemotherapy, the phase 3 MARIPOSA study (NCT04487080) of amivantamab-vmjw (Rybrevant) in combination with lazertinib (Leclaza), the phase 2 RAMOS trial (NCT03909334) of osimertinib and ramucirumab (Cyramza), and the phase 3 PAPILLON trial (NCT04538664) of amivantamab plus chemotherapy.

“The space has rapidly evolved in how we are treating patients, both for the common mutations like exon 19 deletion and L858R, which comprise the majority of EGFR mutations, but also some of the less common mutations such as exon 20 insertions,” Jonathan W. Riess, MD, told Targeted Oncology^TM, in an interview.

In the interview, Riess, medical director of thoracic oncology, University of California, Davis Comprehensive Cancer Center, discussed the ever-changing EGFR-mutated lung cancer treatment landscape, highlighting a number of agents that are currently under development.

Targeted Oncology: What different treatment options are available for patients with EGFR-mutated lung cancer?

Lungs anterior view: © 7activestudio - stock.adobe.com

Riess: The space has rapidly evolved in how we are treating patients, both for the common mutations like exon 19 deletion and L858R, which comprise the majority of EGFR mutations, but also some of the less common mutations such as exon 20 insertions, which are the third most common EGFR activating mutation and some of the less common mutations after that. Starting with the common mutations, the first-line treatment landscape might be rapidly shifting soon. Our standard-of-care in the United States has been osimertinib based upon the FLAURA data that showed robust progression-free survival and overall survival benefit for advanced, EGFR-mutated non–small cell lung cancer with exon 19 deletion and L858R.

[T]his year, there were a number of interesting presentations. We had the FLAURA2 study that brought chemotherapy of carboplatin/pemetrexed that we normally use as second-line [therapy] as standard for these patients and brought it up to [the] first line with osimertinib compared with osimertinib alone which showed a robust progression-free survival benefit, but no clear overall urvival benefit, although it's still early. There was the MARIPOSA study with amivantamab and lazertinib that also showed progression-free survival benefit vs osimertinib. That is another using an EGFR MET bispecific, amivantamab with lazertinib, which is an EGFR TKI with similar but not identical properties to osimertinib. The RAMOS study looked at osimertinib and ramucirumab, adding a VEGF receptor 2 antibody that also showed progression-free survival benefits.

We have all these new regimens, and of course, none are FDA-approved yet, but this highlights that there is the ability to improve progression-free survival and overall survival. It is a bit unclear and I think the key here is, who are the high-risk patients, who are the patients that are going to do poorly with osimertinib alone, whether they have persistent circulating tumor DNA or whether they have co-mutations like p53 or RBM10 that may portend to unfavorable prognosis [central nervous system (CNS)] metastases in FLAURA2. Chemotherapy [with osimertinib] looked a bit better there vs osimertinib alone for PFS tumor burden. I think we'll learn more about how best to apply these regimens. For now, I've still been using osimertinib, but I think the field is evolving rapidly.

What is the current unmet need in the EGFR-mutated lung cancer space?

Right now, the current unmet need is there's no targeted therapies upfront and first line. Our standard-of-care is chemotherapy with carboplatin/pemetrexed backbone. Amivantamab is currently approved as a second-line treatment EGFR MET bispecific antibody [with a] progression-free survival of about 7 months or so, and the updated analysis response rate was approaching about 40%. However, there was the PAPILLON study recently published in the New England Journal of Medicine, where amivantamab was brought upfront with platinum-pemetrexed chemotherapy and showed a PFS benefit of several months and trended towards an overall survival benefit. Not statistically significant, but still, [there are] a lot of events that haven't happened yet. That will probably become statistically significant in the future with a PFS and potentially an overall survival improvement. Bringing amivantamab upfront with chemotherapy and EGFR exon 20 insertions may change the standard-of-care.

There's also a number of EGFR exon 20 tyrosine kinase inhibitors in clinical development that look exciting. Mobocertinib [Exkivity] was approved, but it's being voluntarily withdrawn from the market based upon negative data going up against the first-line setting with platinum-pemetrexed in terms of negative progression-free survival. A number of next-generation exon 20 tyrosine kinase inhibitors are coming to the forefront. There is sunvozertinib [DZD9008] which has CNS penetration activity across a broad spectrum of exon 20 insertion mutations. That looks particularly promising. Furmonetinib [AST2818] is being studied in the first-line setting vs platinum-pemetrexed chemotherapy with a small dataset presented at [the World Conference on Lung Cancer], but [there was an] overall response rate of 75% plus, approaching 80%, and in the second-line setting approaching 50%. Those are exciting developments, so the exon 20 insertion field is also rapidly evolving.

Can you discuss the FAVOUR trial [NCT04858958]?

The FAVOUR trial is looking at furmonertinib, which has activity in EGFR exon 20 insertions. It escalated the dose from what's FDA-approved in China for more common mutations. It's escalating doses up to 240 mg daily. As mentioned in that cohort for EGFR exon 20 insertions, [in the] first line, the response rate was 78.6%, and [in the] second line for previously treated patients was 46.2%. I think that looks to be pretty exciting data looking at an exon 20 insertion drug. It is now being studied first-line, in the FURVENT trial [NCT05607550] compared with platinum-pemetrexed chemotherapy.

What other trials are ongoing in this space?

In terms of additional studies, these exon 20 insertion EGFR TKIs [seem promising], and I think the results of those first-line studies will be informative. We have [PAPILLON] now looking at an amivantamab in that first line with chemotherapy that has moved the bar, but can giving an oral tyrosine kinase inhibitor for exon 20 get a benefit like we see with osimertinib in EGFR common mutations? Looking at the sunvozertinib studies, the furmonertinib study, and others will be quite informative.

What should a community oncologist treating this patient population know about the options available?

One of the take-home points I'll make is to take a look at the type of EGFR-activating mutation. You've got your common exon 19 deletion and L858R where osimertinib is approved, exon 20 EGFR to be able to match that to amivantamab, and then there are some of less common mutations like G719X, L861Q, and others. Some of them have different structures at the end of EGFR. L861Q usually does well with osimertinib, where G719X may not do as well, and afatinib [Gilotrif] is approved. I would say, look for the type of mutation and then try to match that to the most effective therapy or clinical trials.

The other thing to think about is these patients typically don't do well with immunotherapy-based approaches. If you start an EGFR TKI, like osimertinib, after an immunotherapy you are at high-risk of pneumonitis and other adverse events. That's another thing to keep in mind. We don't want to give immunotherapy, at least a single agent to these patients, but even chemotherapy with immunotherapy, giving that off the bat without waiting for the molecular testing, and then if we give osimertinib, we may be risking a higher degree of [adverse] effects in that scenario.