Adjuvant Targeted Therapies Could Continue to Shift the Treatment Paradigm in NSCLC

Alex Adjei, MD, PhD

Adjuvant osimertinib (Tagrisso) has demonstrated efficacy and received FDA approval for treatment following tumor resection in patients with non–small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.¹ Other targeted therapies, such as KRAS G12C inhibitors, could also continue to change the perioperative treatment landscape in NSCLC, according to faculty from an OncLive^® State of the Science Summit™ on lung cancer.

The event, chaired by Alex Adjei, MD, PhD, chair of the Cleveland Clinic’s Taussig Cancer Institute in Cleveland, Ohio, highlighted updates across the NSCLC landscape, including key updates on antibody-drug conjugates (ADCs), treatment for patients with EGFR exon 20 insertion mutations, and the introduction of immunotherapy in the neoadjuvant and adjuvant settings.

Adjei was joined by his colleagues:

• Nathan Pennell, MD, PhD, professor of medicine at the Cleveland Clinic Lerner College of Medicine and medical oncologist in the Department of Hematology and Medical Oncology, at the Cleveland Clinic in Cleveland, Ohio.
• Khaled Hassan, MD, medical oncologist in the Department of Hematology and Medical Oncology, Cleveland Clinic in Cleveland, Ohio.
• Pradnya Patil, MD, medical oncologist in the Department of Hematology and Medical Oncology, Cleveland Clinic in Cleveland, Ohio.
• James Stevenson, MD, vice chairman of the Department of Hematology and Medical Oncology at the Cleveland Clinic’s Taussig Cancer Institute in Cleveland, Ohio.

Below, Adjei, Pennell, Hassan, Patil, and Stevenson summarize their presentations.

Emergence of Adjuvant Osimertinib Highlights Need for Early-Stage Genetic Testing

Pennell: Adjuvant osimertinib [given] for up to 3 years after surgery and adjuvant chemotherapy significantly prolongs disease-free survival [DFS] for stage IB through IIIA EGFR mutation–positive lung cancer. This [DFS] was longer than what we saw with the first-generation [EGFR] inhibitors, along with better central nervous system control. [Adjuvant osimertinib] is [FDA] approved and [is] appropriate to use, pending the final overall survival result, because our patients can’t wait for those results. It may even be cost effective, depending on the magnitude of the benefit.

One thing that is underappreciated in th[is] setting is, if you’re going to use [adjuvant osimertinib], you have to [conduct genetic testing] for patients in the early-stage setting, which is not something that we historically have been set up to do. We’ve been doing that mostly in the stage IV setting. We just submitted an abstract to [the 2023 ASCO Annual Meeting] looking at real-world databases [for] EGFR testing, and it is no great secret that it’s not that high. There is a lot of work to be done in that setting.

Amivantamab-vmjw (Rybrevant) and Mobocertinib (Exkivity) in NSCLC Harboring EGFR Exon 20 Insertion Mutations

Hassan: We have 2 clinical trials [the phase 1 CHRYSALIS trial (NCT02609776) of amivantamab and the phase 1/2 STUDY 101 trial (NCT02716116) of mobocertinib] for the unique [EGFR exon 20 insertion] mutation that previously did not have a good therapy with third-generation TKIs. Both [studies] have comparable outcomes with a median progression-free survival [of 8.3 months for amivantamab and 7.3 months for mobocertinib] and a median overall survival [of 22.8 months for amivantamab and 24.0 months for mobocertinib]. [These outcomes were] much better than the standard of care of chemotherapy, immunotherapy, or third-generation TKIs.

[These agents] have similar adverse effect [AE] profiles. However, mobocertinib had more grade 3 AEs. There were no clear data about brain metastases, but both populations had brain metastases [that were] treated before enrolling in the [respective] clinical trials. We know that amivantamab, as a [bispecific] antibody, has difficulty crossing the blood brain barrier here. Some of the data with mobocertinib suggested that it did not have good control for brain metastases, but that was a small population.

At this point, [amivantamab and mobocertinib are both] good second-line treatments compared with what we had. However, we would like to see more [data for these agents] in first-line treatment and potential combination therapies to have a better use for targeting EGFR exon 20 insertion mutations.

Overcoming Resistance Mechanisms Is Key for Adjuvant and Neoadjuvant Immunotherapy for NSCLC

Patil: We have come a long way [with the use of immunotherapy in the neoadjuvant and adjuvant settings], but there is a long way ahead. There is certainly a lot of work that needs to be done in terms of biomarkers, testing newer combinations, [as well as] trying to better understand primary and acquired resistance and how to target it. We have all these agents; does that mean that it is going to be more accessible for patients globally? Will it bring down health care costs? We haven’t seen that yet. There are certainly a lot of unanswered questions.

There is a lot of research that is ongoing. [There are] multiple clinical trials looking at different strategies to attempt to overcome some of the primary and acquired resistance mechanisms. What we need to be doing is not working harder but working smarter. In an ideal world, it would be nice if we had real-time data, whether it is tissue data or circulating tumor DNA, that will allow us to understand dynamic changes within the tumor and use that information to adapt our treatments accordingly.

We certainly don’t have a miracle cure yet. However, I am hopeful that with all the research that is ongoing, all the science that is backing up clinical trials, and the trials that are being conducted, we have strong rationales for pursuing these treatments. We are hopefully inching closer and closer to a cure.

Perioperative Trials Could Be Next for KRAS G12C Inhibitors

Stevenson: KRAS G12C [is the KRAS mutation that] we have gotten the most clinical action from. [We’ll hear more about] frontline combinations in advanced disease, especially with immunotherapy. How about perioperative trials? We heard about the phase 3 ADAURA trial [NCT02511106] with osimertinib [in EGFR-mutated NSCLC]. [KRAS inhibitors] are going to be used perioperatively as well, potentially in neoadjuvant or adjuvant fashion.

KRAS G12C accounts for about 40% [of KRAS mutations in NSCLC], so there are other KRAS mutations that could be targeted. There are multiple other G12C inhibitors that are in development we’ll hear about, and they are potentially more potent and active than the ones already in use.

ADCs Could Eventually Replace Standard Chemotherapy Options

Adjei: [ADCs] have been studied for over 20 years now [in NSCLC], and now that the chemistry is good and we are finding good antigens, we are getting drugs that are going to be important. My feeling is that if we manage the toxicities, [ADCs] may eventually start taking the place of standard chemotherapy. Instead of doing chemotherapy plus immuno-oncology [IO], we may do more ADCs with IO.

In the setting where patients have mutations, and we have tried all our second- or third-generation TKIs, these ADCs are drugs that are going to be able to be effective across the board. These are going to be very important.

Reference

1. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. News release. FDA. December 18, 2020. Accessed March 8, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations