Spira Highlights Key Advancements Across the NSCLC Treatment Paradigm in 2022

Alexander Spira, MD, PhD, FACP

FDA approvals for nivolumab (Opdivo) plus platinum-doublet chemotherapy in resectable disease, adagrasib (Krazati) in KRAS G12C–mutated locally advanced or metastatic disease, and fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-mutant disease remade treatment for non–small cell lung cancer (NSCLC) in 2022 by. Alexander Spira, MD, PhD, FACP, is excited to see what 2023 holds, especially for agents targeting EGFR mutations.

“There are multiple different drugs, [including] amivantamab [Ryebrevant] and lazertinib [Leclaza],” he said. “Amivantamab is already approved for [EGFR] exon 20 insertion [mutations], but getting it in wider use for typical EGFR mutations will be helpful.”

In an interview with OncLive^®, Spira highlighted the top advancements across NSCLC in 2022, emphasized the need for increased genetic testing to inform treatment decisions, and previewed other agents under development.

Spira is the co-director of the Virginia Cancer Specialists Research Institute and the Phase I Trial Program, the co-chair of the US Oncology Thoracic Oncology Committee, chair of the US Oncology Research Executive Committee, a member of the US Oncology National Policy Board Executive Committee, and an assistant professor of oncology at Johns Hopkins School of Medicine in Baltimore, Maryland.

OncLive^®: What key approvals helped shift NSCLC treatment in 2022?

Spira: Some of the more exciting things [to develop in the lung cancer space involved] neoadjuvant therapy. Neoadjuvant therapy with nivolumab is now the standard of care in all-comers. That is probably the biggest development that we have right now.

Based on the phase 3 CheckMate 816 trial [NCT02998528] data, we now give every patient preoperative chemo-immunotherapy if their tumor is node positive or at least 4 cm, and that's a game changer. Previously, we had the atezolizumab [Tecentriq] data in the adjuvant setting, but this is for all comers.

We did have updated data on KRAS G12C inhibitors. [The data for] adagrasib [Krazati] were published and were very promising, and that may offer a new opportunity for patients [after receiving an accelerated approval by the FDA in December 2022]. Although sotorasib [Lumakras] was already approved, it's good to have 2 drugs in that space.

Overall, those are the 2 biggest things from the 2022 calendar year, in terms of approved drugs and paradigm changes. There are lots of things coming down the pike.

Another notable approval was trastuzumab deruxtecan (Enhertu) in HER2-mutant NSCLC. With has the availability of this targeted agent meant for this subset of patients?

Trastuzumab deruxtecanwas on NCCN guidelines for quite some time. Most clinicians were using it, even without an FDA approval, for at least 6 months to a year beforehand. That has been a game changer for some of those patients, as it works very well. Although the treatment does have some pulmonary toxicity, it has been a game changer for those rare HER2-mutant patients.

As targeted therapy options in NSCLC continue to expand, what are some of the challenges of choosing these agents and which patients can benefit the most?

You can't treat a patient if you don't [conduct genetic testing]. Despite this, we are sorely undertesting and we need to do more. [Testing rates] are getting better, but they are still not where they need to be. [Conducting this testing] is the most important thing. Testing will get complicated in the EGFR world, as a lot of new drugs are coming down from either clinical trials and [and approaching potential] approval. That will complicate things significantly, because you are going to have a plethora of different treatments to offer patients, and we're not going to know which is the right one [without testing].

What are physicians doing to expand access to testing?

Testing has been a challenge [in the lung cancer space]. Breast cancer doctors got this squared away years ago, where you can’t be diagnosed with breast cancer without being checked for estrogen receptor, progesterone receptor, and HER2 [status] every single time. In the lung cancer world, next-generation sequencing [NGS] has been more expensive. NGS is coming down in price, and that will certainly make it more [accessible].

However, the problem is, when it's in physicians’ hands, it never gets done. There are too many reasons why [it doesn’t get done], but we need to have metrics to force physicians to do it. I make the argument that it's better to do it too often than less often. Although we believe that NGS is an expensive test and it's going to come down in price at some point, we have no problem spending thousands of dollars a month on drugs, yet we wonder about ordering these tests to not increase the cost of medicine. The cost of doing those tests is a small fraction of what we're paying in drugs. Giving one patient an inappropriate drug will cost a lot more than [conducting NGS on everyone], even if you’re [overtesting].

Are there any agents in the pipeline that you’re excited about?

There has been some excitement around datopotamab deruxtecan [DS-1062a], which is the anti-TROP2 monoclonal antibody. They completed the randomized phase 3 [TROPION-LUNG01 trial (NCT04656652) of datopotamab deruxtecan] vs docetaxel, so we’re awaiting [data] on that. That will hopefully be in all-comers. There will be subsets looked at both in biomarker-positive and biomarker-negative patients. Now they are beginning to look at that in the frontline setting with various combinations.

Patritumab deruxtecan [U3-1402] is a HER3 drug, but it probably works by inhibiting dimerization with EGFR, or in ways we just don’t understand. There are some great data there with confirmatory randomized studies, as well as combination studies.

We are now participating in studies evaluating [EGFR] C797S [mutations]. C797S is the most common mutation that is seen, and there are some specific drugs that inhibit C797S.

Those are the most exciting things in the EGFR world, in addition to combination therapies. We recently had the approval of a [tremelimumab-actl (Imjudo) plus durvalumab (Imfinzi) and platinum-based chemotherapy for adult patients with metastatic NSCLC without sensitizing EGFR mutations or ALK aberrations], though I don't know how much of a difference that's going to be in the space.

How can clinicians best remain up-to-date on developments in the NSCLC treatment space?

Keeping up his hard, [so the most important thing is] to ask questions of colleagues and other experts. The ultimate take-home message revolves around clinical trials. The second-line treatment for NSCLC, the standard of care, is still one drug: docetaxel. This chemotherapy was approved 20 years ago, and it's a terrible standard of care. It's not well tolerated in the real world, it has a lot of toxicity, and we need to be doing better. Clearly, in the second-line setting, patients should always be considered for clinical studies. [Clinical trials should also be considered] in the frontline setting and for all biomarkers.

The last 2 years have been awful with regard to clinical trials. The challenge that we had was with staffing, patients, and COVID-19. It's a different world, but we still can't lose focus that the best treatment for patients is consideration of a clinical study. Please encourage patients to participate or at least think about participating and be given the option.