Comprehensive NGS Becomes the Gateway to Perioperative NSCLC Targeted Therapy: A Q&A With Jay M. Lee, MD

The primary analysis of the ALK-positive cohort of the phase 2 NAUTIKA1 trial (NCT04302025), presented at the IASLC 2026 World Conference on Lung Cancer (WCLC), showed that 8 weeks of neoadjuvant alectinib (Alecensa) produced a major pathologic response (MPR) in 55.8% of evaluable patients, a pathologic complete response in 18.6%, and downstaging to ypN0 in 31.1%, with a 2-year event-free survival rate of 94% and no new safety signals.¹

It joins the phase 2 ALNEO trial (NCT05015010) of neoadjuvant alectinib in stage III disease and the phase 2 LORIN trial (NCT05740943) of neoadjuvant lorlatinib (Lorbrena) in potentially resectable or unresectable stage III disease as evidence that ALK-directed therapy can be delivered before surgery.

In the second part of an interview with OncLive®, Jay M. Lee, MD, surgical director of the Thoracic Oncology Program at the Jonsson Comprehensive Cancer Center and associate professor of surgery at the David Geffen School of Medicine at UCLA, placed NAUTIKA1 alongside those trials. Lee also explained why comprehensive next-generation sequencing (NGS) is becoming non-negotiable in early-stage disease, previewed the phase 3 targeted therapy trials moving into the perioperative setting, and described how he expects tumor boards to approach early-stage NSCLC 5 years from now.

Part 1 of this interview covers the rationale for neoadjuvant alectinib, the surgical experience in NAUTIKA1, and the role of MPR in risk stratification.

OncLive: Is there anything else you would like to add about NAUTIKA1?

Lee: NAUTIKA1 is complementary to ALNEO, another phase 2 study. NAUTIKA1 is different in that it addressed stage IB to III disease, with select stage IIIB [T3N2] patients, and it allowed chemotherapy in the adjuvant setting: 2 cycles of neoadjuvant alectinib, adjuvant chemotherapy permitted, then 2 years of alectinib. ALNEO was also a phase 2 trial, but only in stage III patients, and chemotherapy was not allowed at all; patients received 2 cycles of neoadjuvant alectinib and then alectinib alone in the adjuvant setting.

The trials are different, but the results are similar. Both are very positive, with clinically meaningful pathologic regression rates and nodal downstaging.

The third trial in this space is LORIN, from China, also a phase 2 study. It addressed a population that was borderline resectable or unresectable, including N3 patients — about half of the patients were N3, which were not included in ALNEO or ALINA. Patients received lorlatinib, a third-generation ALK inhibitor; alectinib is a second-generation agent. We saw very high pCR and MPR rates, and nodal downstaging was extremely high. Again, you are converting borderline resectable patients with a third-generation drug and seeing clinically meaningful pathologic regression and nodal downstaging.

So we now have 3 trials in the early-stage and borderline resectable setting in which patients should get upfront treatment as soon as possible, because it addresses a systemic problem very early on.

OncLive: Does this incentivize timely, sharp diagnostics and immediate referral to care?

Lee: Absolutely. Right now, our standard of care in the early-stage setting is to check PD-L1 and classic EGFR status. With LIBRETTO-432 (NCT04819100) reading out with selpercatinib (Retevmo) for RET fusions, which is going to get FDA approval [editor: verify regulatory status at publication], we now have 4 targets in this space, and phase 3 trials with KRAS G12C are being addressed in the early-stage setting now.

More and more, what we are going to need is full, comprehensive NGS testing in the early-stage setting. You need to know all of these targets before you start chemoimmunotherapy, because there are good drug options for many of these actionable genomic alterations—drugs we use first line in the metastatic setting—and they are all moving up front to early-stage disease.

OncLive: Is there anything else you would like to add, on NAUTIKA1 or otherwise?

Lee: There are other targeted therapy trials coming into this space; they are trials in progress and enrolling, but the movement of small-molecule TKIs into the early-stage setting is increasingly important. One of the phase 3 registrational trials underway addresses HER2 with zongertinib (Hernexeos), which is most effective against tyrosine kinase domain [TKD] mutations. The trial is Beamion LUNG-3 (NCT07195695), and patients receive adjuvant zongertinib.

Because there is no standard of care for HER2 mutations in the early-stage setting, patients are allowed standard-of-care chemoimmunotherapy. They can enter the trial after neoadjuvant chemoimmunotherapy or after upfront surgery. The introduction of the TKI is in the adjuvant setting — zongertinib is given after surgery, chemotherapy is allowed in the adjuvant setting, and zongertinib is randomized against placebo in patients with HER2 TKD mutations. We expect that trial to be positive. That is another trial to look out for.

The other phase 3 study to watch is for patients with EGFR exon 20 insertions, with the small molecule zipalertinib in the REZILIENT trial [editor: confirm trial name/NCT for the early-stage study]. Again, the need for full NGS testing will only become more important as these small molecules address targets for which we currently do not have standards of care in the United States.

OncLive: Five years from now, what do you realistically envision this looking like in practice?

Lee: Five years from now, tumor boards are going to be discussing early-stage patients very similarly to how we think about metastatic patients. What I mean by that is, you are going to need performance status to address whether they can withstand chemotherapy, and then, in the early-stage setting, surgery. You are going to think about the full NGS results — all of the mutations — and the PD-L1 status. You will think about neoadjuvant or adjuvant therapy the way we think about first-line therapy in the metastatic setting.

If the first-line therapy in the metastatic setting is not chemoimmunotherapy, it is not going to be chemoimmunotherapy in the early-stage setting either.

What we hope to see is a drug for each of the actionable genomic alterations that we have drugs for in the metastatic setting. And just as we think about second-line therapy for those targets when metastatic patients progress after first-line treatment, we will think similarly in the early-stage setting, slightly differently: after neoadjuvant therapy and surgery, if a patient has a non-MPR response, we should be thinking about escalated therapies, combination therapies, ADCs plus targeted therapy.

Those are the next-generation trials that are underway. It is analogous to how we think about second-line therapy, but in the early-stage setting.

References

1. Lee JM, et al. NAUTIKA1: Primary Analysis of Neoadjuvant Alectinib in Resectable Stage IB-IIIB ALK+ NSCLC. Presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea.

2. Leonetti A, Boni L, Gnetti L, et al. Alectinib as neoadjuvant treatment in potentially resectable stage III ALK-positive NSCLC: final analysis of ALNEO phase II trial (GOIRC-01-2020-ML42316). J Clin Oncol. 2025;43(suppl 16):8015. doi:10.1200/JCO.2025.43.16_suppl.8015

3. Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: a phase 2 multicenter study (LORIN). J Clin Oncol. 2026;44(suppl 16):8002. doi:10.1200/JCO.2026.44.16_suppl.8002 [editor: add authors]

4. Goldman JW, Yang XN, Hochmair M, et al. Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: primary results of the phase 3 LIBRETTO-432 trial. J Clin Oncol. 2026;44(suppl 17):LBA3. doi:10.1200/JCO.2026.44.17_suppl.LBA3

5. Neoadjuvant Alectinib Yields Responses in Late-Stage, Potentially Resectable ALK+ NSCLC. OncLive. Published June 2, 2025. Accessed September 14, 2026. https://www.onclive.com/view/neoadjuvant-alectinib-yields-responses-in-late-stage-potentially-resectable-alk-nsclc