Neoadjuvant Treatment in ALK-Positive Lung Cancer: What Do ALNEO, NAUTIKA1, and LORIN Show?
In this article
Drug First, Surgery Second: How Tumor-Shrinking Pills Are Changing Surgery in ALK-Positive Lung Cancer
In operable lung cancer, treatment given before surgery (neoadjuvant therapy) has in recent years been built largely on combining chemotherapy with immunotherapy. Patients whose tumors carry an ALK gene fusion, however, do not gain the expected benefit from this approach. For these patients, today's standard is 2 years of alectinib after surgery. Over the past 18 months, the first prospective studies testing the same drug before surgery have reported results: ALNEO from Italy, NAUTIKA1 from the United States, presented at the World Conference on Lung Cancer (WCLC 2026), and LORIN, a lorlatinib study from China. In this article we review preoperative treatment options in detail from the perspective of ALK-positive patients.
- Test first: In stage IB–III non-small cell lung cancer, results for at least ALK and EGFR, and preferably comprehensive next-generation sequencing (NGS), should be available before preoperative chemoimmunotherapy is started. ALK-positive patients were either excluded from chemoimmunotherapy trials or represented in very small numbers.
- Current standard: 2 years of postoperative alectinib. In the Phase 3 ALINA trial, the risk of recurrence or death was reduced by 65% compared with chemotherapy; 4-year disease-free survival was 75.5% versus 47.0%.
- Preoperative targeted therapy: After 8 weeks of alectinib, the major pathological response rate (fewer than 10% of tumor cells remaining viable) was 42% in ALNEO and 56% in NAUTIKA1; with up to 3 cycles of lorlatinib before surgery, it was 81% in LORIN. These are Phase 2 studies without a control arm.
- In practice: Neoadjuvant ALK therapy is not yet approved in any country. In patients with borderline resectable disease or extensive lymph node involvement, it may be considered by a multidisciplinary tumor board, preferably within a clinical trial. In Turkey, postoperative use of alectinib is also not reimbursed by SGK.
Why does this matter?
ALK-positive lung cancer accounts for roughly 3–5% of non-small cell lung cancers. A chromosomal rearrangement fuses the ALK gene with another gene (most often EML4), and the resulting abnormal protein drives the cell to grow continuously. These patients tend to be younger, never or light smokers, and the tumor is most often an adenocarcinoma. Because it is also common in women, awareness of lung cancer symptoms in women is important. The disease also has a marked tendency to spread to the brain: in advanced stages, a substantial proportion of patients develop brain metastases during follow-up.
In advanced ALK-positive disease, oral targeted drugs such as alectinib, brigatinib and lorlatinib have extended survival to a matter of years. The key question is how such effective drugs should be used in early-stage disease, when the chance of cure is highest. In stage II–III disease, the cancer eventually returns in about half of patients despite surgery and chemotherapy. Whether the effective drug should be given after surgery, before it, or both is now one of the most active debates in lung cancer treatment.
No, but for the first time we can draw on prospective trial data:
- 2010s: Case reports and small series of preoperative treatment with crizotinib and alectinib showed that in some patients the tumor could disappear completely (pathological complete response).
- 2024: Based on the Phase 3 ALINA trial, alectinib was approved in the United States and Europe as postoperative (adjuvant) therapy. This was the first targeted therapy approval in early-stage ALK-positive disease and part of a series of practice-changing approvals in lung cancer.
- 2025–2026: ALNEO (ASCO 2025), LORIN (ASCO 2026) and NAUTIKA1 (WCLC 2026) presented the first prospective Phase 2 results of preoperative ALK therapy. Randomized Phase 3 evidence is not yet available.
What is neoadjuvant therapy in ALK-positive lung cancer?
Neoadjuvant therapy is drug treatment given before surgery to shrink the tumor and control undetected spread early. In ALK-positive lung cancer, targeted drugs such as alectinib or lorlatinib are used for 8–12 weeks for this purpose. Phase 2 studies have shown high response rates, but the approach is not yet standard.
Why should testing come first?
Today the most widely used preoperative treatment for operable stage II–III lung cancer is chemotherapy combined with an immunotherapy drug such as nivolumab, pembrolizumab or durvalumab. None of these trials, however, was designed for ALK-positive patients:
- CheckMate 816 (nivolumab + chemotherapy) excluded patients with known EGFR or ALK alterations.
- AEGEAN (durvalumab + chemotherapy) initially enrolled these patients; however, because benefit was limited in both arms, ALK- and EGFR-positive patients were removed from the primary efficacy analysis.
- In trials such as KEYNOTE-671 (pembrolizumab + chemotherapy), the number of ALK-positive patients was too small to draw conclusions specific to this group.
- In the LCMC3 trial of preoperative single-agent atezolizumab, no major pathological response was seen in any tumor carrying an EGFR or ALK alteration.
In advanced disease, too, ALK-positive tumors respond poorly to immunotherapy. In addition, because the effects of immunotherapy can persist for months, serious immune-related adverse events in the liver and lungs have been reported with some targeted drugs started afterwards. In other words, chemoimmunotherapy started before ALK status is known may offer the patient little benefit while adding risk for future treatments. For this reason, international guidelines recommend that ALK and EGFR status be known in every patient for whom preoperative or postoperative immunotherapy is planned.
How is ALK tested?
| Method | What does it show? | Advantage | Caveat |
|---|---|---|---|
| Immunohistochemistry (IHC) | Staining of ALK protein in tissue | Fast, widely available, inexpensive; an approved companion test exists for ALK drugs | Looks only at ALK; does not show other targets |
| FISH | Break-apart of the ALK gene | The standard test for many years | May miss some fusions; requires expertise |
| DNA-based NGS | Simultaneous analysis of dozens of genes, including ALK | Detects targets such as EGFR (including rare subtypes), ROS1, RET, KRAS and HER2 at the same time | Results may take 2–3 weeks; may miss some fusions |
| RNA-based sequencing | Direct detection of the RNA produced by the fusion | Among the most sensitive methods for detecting fusions | Depends on tissue quality; not available at every center |
In practice, the fastest route is to request comprehensive NGS at the same time as ALK IHC on the diagnostic biopsy. In the words of Jay M. Lee, the surgeon who leads NAUTIKA1, all targets need to be known before chemoimmunotherapy is started. When a small biopsy does not provide enough tissue, a blood-based liquid biopsy can be a useful complement.
Postoperative alectinib: the standard ALINA changed
In the Phase 3 ALINA trial, 257 patients with completely resected stage IB (at least 4 cm), II or IIIA ALK-positive disease were randomly assigned to 2 years of postoperative alectinib (600 mg twice daily) or 4 cycles of platinum-based chemotherapy. In the primary analysis published in 2024, the risk of a disease-free survival event (recurrence or death) was reduced by 76% (HR 0.24). In the 4-year update presented at ESMO 2025 and published in 2026, the difference was maintained (HR 0.35).
ALINA: proportion of patients alive without recurrence after surgery
Percentage, all patients. Colored bar: 2 years of alectinib (130 patients); gray bar: 4 cycles of chemotherapy (127 patients).
The risk of recurrence or death was reduced by 76% in the primary analysis (HR 0.24) and by 65% in the 4-year update (HR 0.35). Because alectinib was stopped at 2 years, the proportion of patients alive without recurrence declines between years 3 and 4. Overall survival data are not yet mature.
In absolute terms: at 4 years, about 76 of every 100 patients treated with alectinib were alive without recurrence, compared with 47 of every 100 treated with chemotherapy; in other words, roughly 28–29 fewer recurrences per 100 patients. The difference in brain recurrence was also clear: at 4 years, the rate of survival free of brain recurrence was 90.4% versus 76.1% (HR 0.37). Although 4-year overall survival was 98.4% versus 92.4%, these data are still immature, and most patients in the chemotherapy arm received an ALK drug after recurrence.
A notable point: the recurrence-free rate with alectinib was 88.7% at year 3 but fell to 75.5% at year 4. Because treatment stopped at 2 years, there is an impression that recurrences increase after the drug is discontinued. This strengthens both the question "Are 2 years enough?" and the idea of starting the effective drug earlier, before surgery.
ALINA: safety data
Percentage. Colored bar: alectinib (128 patients); gray bar: chemotherapy (120 patients).
Median treatment duration was 23.9 months for alectinib and 2.1 months for chemotherapy, so adverse events in the alectinib arm accumulated over a much longer period. The most common events were elevated muscle enzyme (CK) and constipation with alectinib, and nausea and loss of appetite with chemotherapy. There were no fatal adverse events.
Preoperative targeted therapy: what do the studies show?
| Study | Drug and duration | Patients | Major pathological response | Pathological complete response | Complete resection (R0) |
|---|---|---|---|---|---|
| ALNEO (Italy, Phase 2) | Alectinib, 8 weeks; then alectinib for up to 2 years | 33 · stage III | 42% | 12% | 86% |
| NAUTIKA1 (USA, Phase 2) | Alectinib, 8 weeks; optional chemotherapy; then 2 years of alectinib | 48 · stage IB–IIIB | 55.8% | 18.6% | 95% |
| LORIN (China, Phase 2) | Lorlatinib, up to 3 cycles; then lorlatinib for up to 2 years | 43 · stage III (24 initially unresectable) | 81.3% | 46.9% | 96.9% |
| West China series (retrospective) | Mostly alectinib, median 5 months | 25 · locally advanced | 36%* | 32% | 100% |
| NeoLORA (China, Phase 2) | Lorlatinib, 6–8 weeks | 25 planned · stage IB–IIIB | Ongoing; results awaited | ||
*In the West China series, the major pathological response rate is reported excluding patients with a complete response; the two combined total 68%. Because the series includes only patients who reached surgery, its results may be optimistic.
Major pathological response with preoperative therapy
Percentage. Fewer than 10% of tumor cells remaining viable at surgery. Colored bars: single-arm studies in ALK-positive patients; gray bar: chemotherapy alone in EGFR-mutated patients.
The gray bar is taken from the randomized NeoADAURA trial in EGFR-mutated (not ALK-positive) patients and is included to illustrate the low pathological response to chemotherapy alone in tumors with a targetable mutation; in the same trial, this rate was 25–26% with osimertinib. Pathological complete response rates: LORIN 46.9%, NAUTIKA1 18.6%, ALNEO 12%. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up differ.
ALNEO: the first prospective result
ALNEO, led by Marcello Tiseo of the University of Parma, enrolled 33 patients with resectable or potentially resectable stage III ALK-positive disease; 82% had involvement of the mediastinal lymph nodes (N2). After 2 cycles (8 weeks) of preoperative alectinib, the tumor shrank substantially in 67% of patients, 85% underwent surgery, and complete removal of the tumor was achieved in 86% of those who had surgery. Nodal downstaging occurred in 48%. Grade 3 adverse events in the preoperative period occurred in 9%; no patient discontinued the drug. At a median follow-up of 20 months, recurrence was seen in 18% of patients.
NAUTIKA1: a broader range of stages
The ALK cohort of the US NAUTIKA1 trial, presented at WCLC 2026, enrolled 48 patients with stage IB–III (selected IIIB) disease. After 8 weeks of alectinib, the major pathological response rate was 55.8%, the complete response rate 18.6%, and complete clearance of the lymph nodes (ypN0) 31.1%. The complete resection rate was 95%. Two-year event-free survival was 94%. The surgical team reported that the operation was not made noticeably more difficult, with low rates of intraoperative complications and hilar adhesions. NAUTIKA1 is also an umbrella trial that includes cohorts for other targets such as ROS1, RET, NTRK and BRAF.
LORIN: bringing inoperable patients to surgery
LORIN, conducted by the Guangdong Lung Cancer Institute, produced the most ambitious results. Lorlatinib, a more potent third-generation drug with better brain penetration, was given for up to 3 cycles. More than half of the patients were initially considered unresectable, and about half had involvement of contralateral or supraclavicular lymph nodes (N3). Of those initially unresectable, 75% were able to undergo surgery. Among the 32 patients who had surgery, nodal downstaging occurred in 90.6%. One-year event-free survival was 97.1%; 3 patients had a regional recurrence and none had a distant recurrence. All patients who relapsed had N3 disease at baseline and had not received postoperative lorlatinib.
Figure 1 · Treatment options in operable ALK-positive lung cancer
A simplified framework, not a strict rule. Decisions are made by a multidisciplinary tumor board.
What should be known about surgery?
- Surgery may become more difficult: While shrinking the tumor, targeted drugs can leave adhesions (fibrosis) in the lymph nodes and at the lung hilum. In reviews, the rate of conversion from minimally invasive (video-assisted) to open surgery after alectinib or crizotinib is about 10%; in an 11-patient series after lorlatinib, moderate-to-severe adhesions were reported in most patients.
- High complete resection rates: Complete resection rates in the studies range from 86% to 100%. No surgery-related mortality was reported.
- Timing matters: The optimal duration of treatment has not been established. ALNEO and NAUTIKA1 used 8 weeks, LORIN 3 cycles, and retrospective series a median of 5 months. Longer treatment may produce more shrinkage, but the risk of resistance and adhesions may also increase.
- Accurate staging: Before treatment, PET-CT, brain MRI and, when needed, lymph node sampling by mediastinoscopy or EBUS affect both the choice of treatment and the subsequent assessment of response.
Which approach for which patient?
| Situation | Current approach | Debated or under investigation |
|---|---|---|
| Stage IA (small tumor) | Surgery and follow-up | No benefit of additional treatment shown; not included in ALINA |
| Stage IB (≥4 cm) – IIIA, clearly resectable | Surgery followed by 2 years of alectinib | Preoperative alectinib; extending treatment beyond 2 years |
| Stage III, extensive N2, borderline resectable | Multidisciplinary board decision; surgery or chemoradiotherapy | Preoperative alectinib or lorlatinib (ALNEO, NAUTIKA1, LORIN) |
| Stage III, unresectable | Chemoradiotherapy, followed by targeted therapy options | Downstaging with lorlatinib and conversion to surgery (LORIN) |
| Patient started on chemoimmunotherapy before ALK status was known | If the result is ALK-positive, treatment is reassessed by the board | Watch for adverse-event risk with targeted drugs after immunotherapy |
Side effects and follow-up
- Alectinib: The most common effects are elevated muscle enzyme (CK), constipation, muscle pain, raised liver enzymes, weight gain, slowed heart rate and photosensitivity. Liver tests and CK are monitored regularly; sun protection is recommended.
- Lorlatinib: Elevated cholesterol and triglycerides, edema, weight gain, numbness in the fingers and toes (peripheral neuropathy) and, in some patients, changes in mood, sleep or memory. Blood lipids are measured regularly and are controlled with medication in most patients. Possible mood changes should be explained to patients and their families in advance.
- Drug interactions: Both drugs are metabolized in the liver. Herbal products, St John's wort and certain medicines for the stomach, epilepsy or infections can alter their blood levels; patients should consult their oncologist before starting any new medicine.
- Postoperative follow-up: In addition to chest CT, brain MRI is an important part of follow-up. Detecting recurrence early and personalizing treatment duration using circulating tumor DNA (ctDNA) are under investigation.
- Physical preparation: Breathing exercises and physical activity before surgery make postoperative recovery easier.
Alectinib, brigatinib and lorlatinib are licensed in Turkey. Postoperative (adjuvant) use of alectinib is included in the approved Turkish label, but the SGK reimbursement list covers only uses in advanced disease; in other words, 2 years of postoperative alectinib is among the licensed but non-reimbursed uses. Under the SUT rules, ALK drugs are reimbursed in advanced disease with a health board report and in a defined sequence. Preoperative alectinib or lorlatinib, by contrast, is not approved in any country; in Turkey it is possible only with off-label use authorization from TİTCK, and obtaining reimbursement is difficult. For non-reimbursed uses, some patients turn to legal routes. For eligible patients, clinical trials abroad, or ones that may open in Turkey, can also be an option.
Practical advice for patients and families
- Before any decision about surgery or preoperative treatment, make sure your biopsy report includes ALK, EGFR and PD-L1 results; if not, ask for them.
- Results can take 2–3 weeks. This waiting period generally does not affect the outcome; it is safer than starting the wrong treatment.
- Ask for your treatment plan to be discussed at a board where a thoracic surgeon, medical oncologist, radiation oncologist and pulmonologist assess it together. If needed, get a second opinion.
- Take targeted drugs at the same time every day, with food (alectinib) or as instructed; do not skip doses, and report side effects early.
Frequently asked questions
- Is immunotherapy given before surgery in ALK-positive lung cancer?
- Generally not recommended. ALK-positive patients were either excluded from preoperative chemoimmunotherapy trials or included in very small numbers, and the benefit in these patients appears limited. For this reason, ALK and EGFR test results should be available before treatment begins.
- Is alectinib before surgery a standard treatment?
- Not yet. Phase 2 studies such as ALNEO, NAUTIKA1 and LORIN have shown high response and complete resection rates, but there is no randomized Phase 3 evidence and it is not approved in any country. The current standard is 2 years of alectinib after surgery.
- How long is alectinib taken after surgery?
- In the ALINA trial it was given for 2 years and clearly reduced the risk of recurrence compared with chemotherapy. Because recurrences appear to increase after the drug is stopped, the benefit of longer treatment is being studied; for now, the recommended duration is 2 years.
- Is postoperative alectinib reimbursed by SGK in Turkey?
- No. Postoperative use of alectinib is included in the approved Turkish label, but SGK reimburses only its use in advanced ALK-positive lung cancer. Preoperative use is off-label.
Glossary
- ALK fusion
- Joining of the ALK gene with another gene; an abnormal protein that drives tumor growth is produced and can be blocked with targeted drugs.
- Neoadjuvant therapy
- Drug treatment or radiotherapy given before surgery.
- Adjuvant therapy
- Treatment given after surgery to reduce the risk of recurrence.
- Major pathological response (MPR)
- Fewer than 10% viable cancer cells remaining in the surgically removed tumor.
- Pathological complete response (pCR)
- No viable cancer cells in the surgically removed tumor and lymph nodes.
- R0 resection
- Complete surgical removal of the tumor with no cancer cells at the surgical margins.
- N2 / N3
- N2: involvement of mediastinal lymph nodes on the same side; N3: involvement of lymph nodes on the opposite side or above the collarbone (supraclavicular).
DROZDOGAN Academy Commentary
Early-stage ALK-positive lung cancer is one of the clearest examples of why the "same preoperative treatment for every patient" approach is being left behind.
⚡ Why it matters
At a time when preoperative chemoimmunotherapy is becoming widespread, treatment started without waiting for the ALK result may bring the patient little benefit and additional risk. On the other hand, giving the most effective drug before surgery removes the 4–6 month delay that follows chemotherapy and opens the possibility of surgery for some patients who were initially unresectable.
✅ Strengths
Adjuvant alectinib is supported by randomized Phase 3 evidence and 4 years of follow-up. Preoperative studies from different countries, using different drugs, show consistent results: high response rates, high complete resection rates and acceptable side effects.
⚠️ Limitations
Preoperative data come from Phase 2 studies of 25–48 patients without a control arm, and follow-up is short. How well major pathological response predicts long-term survival in ALK-positive patients is unknown. The LORIN and NAUTIKA1 data are still conference presentations. Overall survival in ALINA is not yet mature.
🩺 In practice
In every early-stage adenocarcinoma, ALK and EGFR results, preferably from comprehensive NGS, should be awaited before treatment. For clearly resectable patients, the standard is surgery and 2 years of alectinib. In borderline resectable disease or extensive N2 or N3 disease, preoperative targeted therapy is an option that can be discussed at an experienced center, preferably within a clinical trial.
❓ Open questions
How many weeks should preoperative treatment last? Alectinib or lorlatinib? Is adjuvant chemotherapy needed after preoperative treatment? Are 2 years enough, or is longer, ctDNA-guided treatment needed? Will a randomized trial compare pre- and postoperative targeted therapy with postoperative therapy alone?
Bottom line: In early-stage ALK-positive lung cancer, the first and most important step is testing. Postoperative alectinib is today's standard; preoperative alectinib and lorlatinib are an option for tomorrow that shows strong signals but is not yet proven.
- This article was prepared in October 2026.
- ALINA data are based on the NEJM (2024) publication, the ESMO 2025 presentation and the Lancet Oncology (2026) publication. ALNEO data are taken from the ASCO 2025 abstract, LORIN data from the ASCO 2026 abstract, and NAUTIKA1 data from news reports on the WCLC 2026 presentation; LORIN and NAUTIKA1 have not yet been published in full in a peer-reviewed journal.
- Information on ALK-positive patients in chemoimmunotherapy trials is taken from review articles. Turkish reimbursement information is based on the SUT as of October 2026 and may change.
- The comparisons in the preoperative major pathological response chart come from different studies and are indirect; the ALINA charts compare randomized arms of the same trial. The diagram is derived from the text and contains no new data. The Academy commentary is our own.
References
- Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in resected ALK-positive non-small-cell lung cancer (ALINA). N Engl J Med 2024;390:1265-1276. PubMed
- OncLive. Adjuvant alectinib impresses in updated ALINA results for ALK+ NSCLC (ESMO 2025, October 20, 2025). onclive.com
- Targeted Oncology. Adjuvant alectinib maintains manageable safety, QoL in NSCLC (Lancet Oncol 2026;27(9):1110-1119). targetedonc.com
- ASCO Post. Adjuvant alectinib improves survival vs platinum-based chemotherapy in ALK-positive NSCLC (2024). ascopost.com
- Tiseo M, Leonetti A, Boni L, et al. ALNEO final analysis. J Clin Oncol 2025;43(16_suppl):8015. onclive.com · targetedonc.com
- OncLive. Neoadjuvant alectinib moves the best systemic therapy up front in resectable ALK+ NSCLC: a Q&A with Jay M. Lee, MD (NAUTIKA1, WCLC 2026; September 14, 2026). onclive.com
- OncLive. Comprehensive NGS becomes gateway to perioperative targeted therapy in NSCLC: Q&A with Jay M. Lee, MD (September 14, 2026). onclive.com
- Zhang C, Hu Y, Jiang BY, et al. Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: a phase 2 multicenter study (LORIN). ASCO 2026, Abstract 8002. hmpgloballearningnetwork.com
- Lorlatinib as neoadjuvant treatment in stage IB-IIIB ALK-rearranged NSCLC (NeoLORA). ESMO ELCC 2025, study abstract. oncologypro.esmo.org · NCT06682884
- Wu J, Li Z, Yang Z, Liu C. Neoadjuvant ALK tyrosine kinase inhibitor in patients with resectable locally advanced NSCLC harboring ALK rearrangement. Transl Lung Cancer Res 2026;15(2):39. tlcr.amegroups.org
- Neoadjuvant, adjuvant and perioperative treatment in early-stage NSCLC with actionable genomic alterations: current landscape and future perspectives (review). PMC
- OncLive. Neoadjuvant osimertinib yields MPRs with or without chemotherapy in resectable EGFR-mutated NSCLC (NeoADAURA, ASCO 2025). onclive.com
- U.S. FDA. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer (April 18, 2024). fda.gov
- ClinicalTrials.gov. ALINA (NCT03456076). clinicaltrials.gov
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