Treatment Sequencing Clarifications May Spur NSCLC Therapeutic Evolutions

Ongoing research for patients with lung cancer, particularly those with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, is looking to identify the optimal treatment sequence with approved agents amivantamab-vmjw (Rybrevant) and mobocertinib (Exkivity), and the investigational EGFR inhibitor CLN-081, according to Angel Qin, MD, who stated that current decision-making in the second line is being guided by the toxicity profiles of frontline chemoimmunotherapy regimens, according to Angel Qin, MD.

“The uptake of next-generation sequencing [NGS] is necessary, not only in stage IV disease, but now in all stages of NSCLC,” Qin said in an interview with OncLive® following a State of the Science Summit™ on lung cancer, which she chaired.

In the interview, Qin discussed factors influencing treatment decisions with amivantamab and mobocertinib in patients with EGFR exon 20–mutated NSCLC, highlighted ongoing research seeking to address remaining unmet needs in this population, and emphasized the importance of using NGS results to determine appropriate therapies for patients with NSCLC based on their genetic profiles. 

In May 2021, the FDA approved amivantamab for adult patients with EGFR exon 20­–mutated NSCLC.¹ In September 2021, mobocertinib received an accelerated FDA approval for patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.² Qin compared the efficacy and safety of these 2 agents and noted areas of continued research with these and other drugs in this population.

Moreover, Qin contextualized the NSCLC treatment landscape in light of updated findings from the phase 3 ADAURA trial (NCT02511106), in which patients with EGFR-mutated NSCLC who received adjuvant therapy with osimertinib (Tagrisso) achieved a 5-year overall survival (OS) rate of 85% vs 73% in those who received placebo (HR, 0.49; 95.03% CI, 0.33-0.73; P < .001).³

Qin is a clinical assistant professor at the University of Michigan Health Rogel Cancer Center in Brighton.

OncLive: How do EGFR exon 20 mutations compare with other EGFR alterations found in NSCLC?

Qin: Exon 20 mutations are rare among EGFR [alterations], but they behave differently than the classical EGFR mutations, L858R [mutations] and exon 19 deletions. [Patients with exon 20] mutations should not be treated in the same way [as patients with classical EGFR mutations]. We should learn to recognize the existence of [those] mutations. There are 2 FDA-approved agents for [exon 20] mutations, amivantamab and mobocertinib. However, their approvals are in the second-line setting. 

How have you worked with pathologists to interpret NGS reports and identify EGFR exon 20 mutations in NSCLC?

When we see EGFR [mutations] reported on an NGS sequencing report, our knee jerk reaction is that [this is a disease in which] we could use a classical EGFR inhibitor. I’ve been lucky that our pathologists [at Rogel Cancer Center] have been wonderful, and they carefully spell out what this mutation is. For those of us who are not well versed in molecular biology or don’t remember the days of biochemistry, that nomenclature can be difficult to interpret on an NGS report. Our pathologists have been wonderful in spelling that out. In commercial products, [I’ve also seen] the types of EGFR mutations spelled out much more carefully.

How do you decide whether to use amivantamab or mobocertinib in patients with EGFR exon 20 mutations? Does the choice of frontline therapy affect which agent you pursue?

We don’t know whether one agent is superior to the other regarding sequencing. [We discuss with patients [to see whether they prefer] intravenous infusions or an oral pill, and then [we consider the] adverse effect profile [of each agent]. Rash and infusion reactions may be more [common] with amivantamab, and more diarrhea [may occur] with mobocertinib.

Right now, we also don’t have great data to suggest that if patients had either prior chemotherapy or prior chemoimmunotherapy as their frontline therapy, 1 or the other agents should be used. Understanding the toxicities patients may have experienced with their prior treatment may sway your decision regarding whether you choose mobocertinib or amivantamab.

What ongoing clinical trials are investigating novel agents for patients with EGFR exon 20–mutated disease?

[Several] clinical trials are evaluating agents that are perhaps a bit better tolerated [than amivantamab and mobocertinib]. Cullinan Oncology, LLC, has a study [NCT04036682] investigating whether patients who have progressed on amivantamab or mobocertinib can move on to CLN-081 as a sequential treatment.

Right now, I haven’t seen too many EGFR exon 20 [inhibitors] in the frontline setting, because none of the agents we have so far have response rates that are as impressive as what we’ve seen with chemoimmunotherapy. Additionally, with EGFR exon 20 mutations, like with classical EGFR mutations, brain metastases are a significant area of morbidity. However, as of now, neither amivantamab nor mobocertinib have great intracranial penetrance. Some of those hurdles [may be] limiting frontline use of EGFR exon 20–directed agents. However, I’m sure this is [an area that researchers] are working on.

What does the future look like for NSCLC management, and how do these projections highlight unmet needs in patients with small cell lung cancer (SCLC)?

Lung cancer treatment continues to change. Although I started as faculty [at Rogel Cancer Center] in 2018, what I knew about lung cancer then is not what we [know] now. One big highlight in lung cancer today is the different drivers we now have in the frontline and second-line settings, which is an impressive list, as well as the ever-growing list of available agents for each of these drivers. [We also know more about] resistance mutations and resistance in general.

Sequencing of these drugs is 1 important area of discussion. With some drivers like EGFR and ALK, immunotherapy is not effective. We don’t understand why, but we are trying to understand the role of immunotherapy for some of these other drivers.

The other big advancement in NSCLC is perioperative treatment, [including] neoadjuvant chemoimmunotherapy, adjuvant immunotherapy, and then more recently published, perioperative chemoimmunotherapy and immunotherapy. We’re trying to understand: Are these strategies equivalent? Do they offer the same benefit? What are we missing when selecting the optimal patients for these treatment strategies? Additionally, with targeted therapies [for] molecularly driven [patient] subsets, there’s much interest in looking at neoadjuvant and adjuvant approaches with TKIs, especially in the setting of a positive OS readout from the ADAURA study.

Unfortunately, for SCLC, which [many clinicians] tend to forget about or maybe don’t want to think about, since the addition of frontline immunotherapy to chemotherapy, we haven’t made huge headways in extending OS. The questions that have been raised are: Should we now try to molecularly profile SCLC the same way that we do NSCLC? [Would that] allow us to better select therapies? That’s an active area of research, and it’s an area we need to stress because we’ve made much progress in NSCLC, but SCLC is lagging.

When should genetic testing be done for patients with resectable disease to ensure they receive effective therapies or appropriate clinical trial opportunities?

For patients with all stages of resectable lung cancer, or lung cancer in general at this point, especially adenocarcinoma and even squamous cell carcinoma, NGS and PD-L1 testing are warranted. Immunotherapy does not work well for EGFR-positive NSCLC. If I were to find patients with [EGFR-positive disease], I would highly consider them for the [phase 3] NeoADAURA trial [NCT04351555], which is investigating neoadjuvant osimertinib [with or without chemotherapy vs chemotherapy alone]. I would not recommend that they receive neoadjuvant chemotherapy plus nivolumab [Opdivo], [which is] the [phase 3] Checkmate 816 [trial regimen (NCT02998528)].

Additionally, with adjuvant studies, we certainly would not recommend patients receive adjuvant immunotherapy if they have EGFR, ALK, or maybe other driver mutations. Instead, they should either consider a clinical trial or [the ADAURA regimen if they have a classical EGFR mutation].

Disclosures: Dr Qin reports institutional research funding from Merck, Clovis, AstraZeneca, Genentech, and Xencor; and advisory board participation with Amgen.

References

1. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed July 24, 2023. https://www.prnewswire.com/news-releases/fda-approves-first-targeted-therapy-for-subset-of-non-small-cell-lung-cancer-301296998.html
2. Takeda’s EXKIVITY (mobocertinib) approved by US FDA as the first oral therapy specifically designed for patients with EGFR exon20 insertion+ NSCLC. News release. Takeda Pharmaceutical Company. September 15, 2021. Accessed July 24, 2023. https://www.takeda.com/newsroom/newsreleases/2021/takeda-exkivity-mobocertinib-approved-by-us-fda/
3. Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. 2023;389(2):137-147.doi:10.1056/NEJMoa2304594