Neoadjuvant Alectinib Moves the Best Systemic Therapy Up Front in Resectable ALK+ NSCLC: A Q&A With Jay M. Lee, MD

Adjuvant alectinib (Alecensa) is the standard of care for resected stage IB - IIIB ALK-positive non–small cell lung cancer (NSCLC) on the strength of the phase 3 ALINA trial (NCT03456076), but the design of that trial left open where chemotherapy fits, and in practice many patients complete surgery and adjuvant platinum-based chemotherapy before starting a targeted agent months later. NAUTIKA1 (NCT04302025), a phase 2 umbrella study in biomarker-selected resectable NSCLC, tested whether that sequence can be reversed.

At the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul this week, investigators presented the primary analysis of the full ALK-positive cohort (N = 48).¹ Patients with stage IB - IIIB (T3N2 only) disease received 8 weeks of neoadjuvant alectinib at 600 mg twice daily, then surgery, optional platinum-based chemotherapy, and 2 years of adjuvant alectinib.

The primary end point, major pathologic response (MPR), was achieved in 55.8% of evaluable patients (n = 24), with a pathologic complete response (pCR) in 18.6% (8/43). The radiographic objective response rate was 60.0% (n = 27), 37.8% of patients (n = 17) were clinically downstaged, and 31.1% (n = 14) were downstaged to ypN0.

R0 resection was achieved in 95% (n = 40). At a median follow-up of 20.8 months, the 2-year event-free survival (EFS), disease-free survival (DFS), and overall survival rates were 94%, 96%, and 97%, respectively, with no new safety signals.

In the first of a 2-part interview with OncLive® while at WCLC 2026, study author 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, discussed the rationale for the neoadjuvant approach, what the surgical experience looked like, how to weigh the contribution of the neoadjuvant and adjuvant phases, and whether he would offer neoadjuvant alectinib to a patient today.

OncLive: How do the NAUTIKA1 findings presented at WCLC 2026 affect practice for clinicians who encounter these patients?

Lee: The current standard of care for resectable ALK-positive NSCLC is adjuvant targeted therapy: upfront resection followed by adjuvant alectinib, which became the standard and received FDA approval based on the ALINA trial. There is an unmet need for patients, particularly those with stage III disease, but also stage II patients, when we know they are node-positive. What do you do with patients who need upfront treatment with a neoadjuvant or perioperative approach?

One of the downsides of ALINA is that it excluded chemotherapy; the comparator arm was adjuvant alectinib vs adjuvant chemotherapy. Many clinicians, particularly medical oncologists, asked where chemotherapy fits in that standard of care. What has happened in the real-world setting is that patients have received chemotherapy after surgery first as a standard of care, then started alectinib, even though that was not the ALINA trial design. With that approach, patients go through surgery, recover, get through 3 or preferably 4 cycles of platinum-based chemotherapy, and then start alectinib. This is very similar to the ADAURA design for classic EGFR mutations in the early-stage setting, and essentially patients are waiting 4 to 6 months before they start the best systemic therapy agent.

The rationale for the neoadjuvant approach is to move the best systemic agent up front. NAUTIKA1 addresses that. It is a single-arm phase 2 trial in which we give 2 cycles of neoadjuvant alectinib, so that patients get a head start on drug therapy, particularly at higher stages, then go to surgery, receive standard-of-care chemotherapy, and continue alectinib for 2 years, as in ALINA. The real impact is the idea of moving up your best systemic therapy as soon as possible.

OncLive: Does neoadjuvant alectinib make the operation easier or harder?

Lee: I do not think it makes it any harder. We did not have a comparator arm in NAUTIKA1, but we collected data on intraoperative complications and on the inherent difficulty of the operation related to perihilar fibrosis, and all of those numbers were in the low single digits. It does not seem to affect the conduct of the surgery.

For surgeons who operated before immunotherapy and targeted therapy, in the era of neoadjuvant chemotherapy or chemoradiation for stage III disease, perihilar fibrosis and inherent difficulty were expected. How much of that was driven by locally advanced disease and how much by the drugs themselves was unclear even before the chemoimmunotherapy era.

As a surgeon, I do not see much difference between an induction chemoradiation case and an induction chemoimmunotherapy or induction targeted therapy case. The short answer is no; we did not see an increase in the difficulty of the operations in NAUTIKA1.

OncLive: Every patient in NAUTIKA1 also received 2 years of adjuvant alectinib, which ALINA has already shown works well in this population. How do you separate what the 8 weeks of neoadjuvant therapy contributed from what the 2 years of adjuvant therapy contributed?

Lee: The issue with any perioperative design is the contribution of phases. The largest study of targeted therapy in the early-stage setting is NeoADAURA (NCT04351555) for EGFR, with 3 arms: chemotherapy plus osimertinib (Tagrisso), osimertinib alone, or chemotherapy alone for 9 weeks in the neoadjuvant setting, followed by surgery and standard-of-care therapy.

Because ADAURA (NCT02511106) established that patients receive 3 years of adjuvant osimertinib, how is 9 weeks going to lead to a survival difference among 3 arms that all essentially receive 3 years of adjuvant osimertinib? It is hard to envision any survival difference.

The main take-home message from a neoadjuvant or perioperative approach is the early separation between MPR and non-MPR. You see it in NeoADAURA: the Kaplan-Meier curves for EFS split very early, and the poor responders to osimertinib are the non-MPR patients. That is the main contribution—identifying patients who are not going to do as well with a mono-targeted approach, because the next generation of trials will escalate therapy in non-MPR patients. It is the same in NAUTIKA1. We saw a 56% MPR rate, and MPR status is an easy, early identifier of responders and lesser responders to alectinib. I do not think you will see a survival difference, but you get quick risk stratification.

This is analogous to how medical oncologists think about the first-line EGFR setting: do you give osimertinib monotherapy, or an escalated regimen like FLAURA2 (NCT04035486) or MARIPOSA (NCT04487080)? More and more, the shift is to identify high-risk patients in EGFR—TP53, liver and brain metastases—as the core prognostic indicators and the rationale for escalated therapies.

In the early-stage setting, I do not know who is going to have a metastasis to the brain or to the bone—we can measure TP53 or bone or liver metastases—but MPR vs non-MPR becomes the risk stratification that we are looking for in the metastatic setting. It is the early-stage equivalent.

The other advantage of the neoadjuvant approach, besides trying to show a survival difference, is that with neoadjuvant alectinib we saw a 30% pathologic nodal downstaging. It clears the locally advanced nodal disease [to N0] 30% of the time. Earlier therapy initiation with your best systemic therapy agent and pathologic downstaging to N0 status with just 2 cycles of neoadjuvant alectinib are all beneficial things for the patient, along with CNS protection. You are giving that drug so early that for the early progressors, you are not waiting until 6 months after surgery to give your best systemic therapy agent. You are protecting the CNS, downstaging the nodes, and getting clinically meaningful MPR.

Although none of that is going to equate to a survival difference for the neoadjuvant component, those are all very good things for the patient, and this is also true for other TKIs. Those are the hallmark highlights of a perioperative design.

OncLive: Is there a patient in front of you right now for whom you would argue for the neoadjuvant approach, or does this stay investigational until there is a randomized comparison?

Lee: A single-arm phase 2 study is unlikely to get FDA registration. The next best thing is endorsement from professional societies like the NCCN to say that it is an acceptable standard or an option for patients. If I saw a patient with stage II or III disease today, would I recommend neoadjuvant therapy? Absolutely. I think it is the right thing to do.

If you think about how you would get FDA registration with a neoadjuvant approach, it is hard to envision showing a survival difference, and that is where we are stuck with NeoADAURA right now. Registration based on the neoadjuvant portion alone is unlikely. Because of this, endorsement from organizations like the NCCN, ASCO, and ESMO guidelines would be helpful, so that treating physicians are aware that this is an option, that it is feasible and safe, and that we get meaningful efficacy by pathologic regression, nodal downstaging, and CNS protection—that this is a meaningful thing to do for patients, to give your best drug therapy as early as possible when stage II and III patients have such high relapse rates, mostly systemic, so it becomes a systemic disease.

So why do aggressive surgery up front? Treat the whole body and treat the systemic relapse risk as early as possible.

Part 2 of this interview covers how NAUTIKA1 compares with ALNEO and LORIN, the case for comprehensive NGS in early-stage disease, and the targeted therapy trials moving into the perioperative 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. Adjuvant Alectinib Impresses in Updated ALINA Results for ALK+ NSCLC. OncLive. Published October 20, 2025. Accessed September 14, 2026. https://www.onclive.com/view/adjuvant-alectinib-impresses-in-updated-alina-results-for-alk-nsclc