A New Chemotherapy-Free Era in PD-L1-Negative Lung Cancer? OptiTROP-Lung06 and ESMO 2026
In this article
Chemotherapy-Free First-Line Treatment for PD-L1-Negative Lung Cancer: Sac-TMT + Pembrolizumab Extended Progression-Free Survival From 5.7 to 15 Months
The OptiTROP-Lung06 trial, presented by Prof. Caicun Zhou as a late-breaking abstract (LBA66) in the lung cancer session of ESMO 2026 and published the same day in the New England Journal of Medicine, proposes a new approach for advanced lung cancer in which no PD-L1 is detected in the tumor (PD-L1-negative) and there is no targetable mutation. The TROP2-directed antibody–drug conjugate sacituzumab tirumotecan (sac-TMT), given together with the immunotherapy drug pembrolizumab, extended median progression-free survival from 5.7 to 15.0 months compared with today's standard, chemotherapy + pembrolizumab. We have covered the ESMO 2026 agenda ahead of the congress, the results in EGFR-mutant lung cancer presented at the same congress, pembrolizumab and WCLC 2026 in separate articles.
- Who it is for: Previously untreated, advanced, non-squamous (mostly adenocarcinoma) non-small cell lung cancer without targetable alterations such as EGFR/ALK and with a PD-L1 tumor proportion score below 1%.
- Result: In a phase 3 trial of 455 patients, sac-TMT + pembrolizumab reduced the risk of progression by 51% compared with platinum-pemetrexed + pembrolizumab (HR 0.49); median progression-free survival was 15.0 vs 5.7 months. At 12 months, about 51% vs 23% of patients were progression-free.
- Survival and side effects: Overall survival data are not yet mature, but the trend is favorable: at 12 months, 77.6% vs 66.4% of patients were alive (HR 0.58). Grade ≥3 side effects were less frequent (47.6% vs 60.6%); the most common problem was mouth sores (stomatitis), mostly mild to moderate.
- Turkey: Sacituzumab tirumotecan is not approved in Turkey, the US or Europe; it is approved only in China. In Turkey, chemotherapy + pembrolizumab remains the standard treatment.
Why does this matter?
In about one third of non-small cell lung cancers, no PD-L1 protein is detected on the tumor cells. In these patients, immunotherapy alone is not enough; the standard treatment is therefore immunotherapy given together with chemotherapy (proper planning in immunotherapy). In the KEYNOTE-189 trial, adding pembrolizumab to platinum-pemetrexed chemotherapy prolonged survival in the PD-L1-negative subgroup as well (HR 0.59). However, the treatment effect in this group is more limited than in PD-L1-positive patients, and the disease usually progresses within the first year.
Antibody–drug conjugates are "smart" drugs that use an antibody to deliver a chemotherapy molecule directly to the tumor cell (antibody–drug conjugates). TROP2 is a surface protein found at high levels in most lung cancers. OptiTROP-Lung06 tested whether replacing classic chemotherapy with a TROP2-directed conjugate could achieve better results in this difficult-to-treat patient group.
According to the manufacturer, OptiTROP-Lung06 is the first phase 3 trial testing an antibody–drug conjugate + immunotherapy combination to meet its primary endpoint in the first-line setting in PD-L1-negative non-squamous lung cancer without targetable mutations. How did we get here?
What does sacituzumab tirumotecan + pembrolizumab offer in PD-L1-negative lung cancer?
In OptiTROP-Lung06, in the first-line treatment of PD-L1-negative advanced non-squamous lung cancer without targetable mutations, sacituzumab tirumotecan + pembrolizumab extended median progression-free survival from 5.7 to 15.0 months compared with platinum-pemetrexed + pembrolizumab (HR 0.49). Serious side effects were less frequent. Survival data are not yet mature, and the drug is not approved in Turkey.
Figure 1 · Design of the OptiTROP-Lung06 trial
Open-label, randomized phase 3 trial
How was the trial conducted?
OptiTROP-Lung06 is an open-label, randomized phase 3 trial sponsored by Kelun-Biotech, conducted in China and led nationally by Prof. Caicun Zhou of Shanghai. The trial enrolled 455 patients with locally advanced (stage IIIB/IIIC) or metastatic (stage IV) non-squamous non-small cell lung cancer who had received no prior treatment for advanced disease, had no sensitizing EGFR mutation or ALK alteration, had a PD-L1 tumor proportion score below 1% measured at a central laboratory (22C3 assay) and were in good general condition (ECOG 0–1). Randomization was stratified by sex, performance status and stage (differences between small cell and non-small cell lung cancer).
- Experimental arm (229 patients): Sacituzumab tirumotecan 4 mg/kg every 2 weeks + pembrolizumab 400 mg every 6 weeks; no chemotherapy.
- Control arm (226 patients): Pemetrexed + carboplatin or cisplatin every 3 weeks (platinum up to 4 doses), followed by pemetrexed + pembrolizumab maintenance; pembrolizumab 400 mg every 6 weeks. Today's standard treatment.
- Treatment duration: Until disease progression or unacceptable side effects; pembrolizumab for up to 18 cycles (about 2 years).
- Primary endpoint: Progression-free survival by blinded independent central review. Overall survival was a secondary endpoint.
- Assessment: Tumors were imaged every 6 weeks in the first year, then every 12 weeks. The results come from a prespecified interim analysis; median follow-up was 9.7 months.
Results
| Outcome | Sac-TMT + pembrolizumab | Chemotherapy + pembrolizumab | Difference |
|---|---|---|---|
| Progression events | 79 patients (34.5%) | 126 patients (55.8%) | – |
| Median progression-free survival (independent review) | 15.0 months (95% CI 9.9–not estimable) | 5.7 months (95% CI 5.5–7.4) | HR 0.49 (95% CI 0.36–0.65); p<0.0001 |
| Progression-free survival (investigator assessment) | Consistent with independent review | HR 0.52 (95% CI 0.40–0.69) | |
| Progression-free at 12 months | 51.1% | 22.8% | About 28 points |
| Objective response rate | 50.2% | 47.3% | Similar |
| Median duration of response | 13.6 months | 6.8 months | About 2-fold |
| Survival events | 36 patients (15.7%) | 55 patients (24.3%) | – |
| Proportion of patients alive at 12 months | 77.6% | 66.4% | About 11 points |
| Median overall survival | Not reached | Not reached | HR 0.58 (95% CI 0.38–0.88); descriptive |
| Grade ≥3 side effects | 47.6% | 60.6% | Fewer in the experimental arm |
Source: NEJM publication and ESMO 2026 presentation (LBA66). CI: confidence interval. An HR of 0.49 means a relative reduction of about 51% in the risk of progression or loss of life over follow-up.
Progression-free survival
Median progression-free survival (months), blinded independent central review. Colored bar: sac-TMT + pembrolizumab; grey bar: chemotherapy + pembrolizumab.
HR 0.49 (95% CI 0.36–0.65); p<0.0001. Median follow-up 9.7 months; prespecified interim analysis.
How large is the absolute difference?
At 12 months, the disease had not progressed in about 23 of every 100 patients receiving chemotherapy + pembrolizumab, compared with about 51 of every 100 receiving sac-TMT + pembrolizumab. In other words, about 28 of every 100 patients spent a year without progression thanks to the new combination.
Figure 2 · Out of every 100 patients, how many were progression-free at 12 months?
Values rounded from the 12-month rates (51.1% and 22.8%) in the ESMO 2026 presentation
Similar response rate, twice the duration of response
One of the trial's most striking findings is that the rate of tumor shrinkage was almost the same in both arms (50% vs 47%). The difference lies in how long the response lasted: among responders, the response lasted a median of 13.6 months in the sac-TMT arm and 6.8 months in the chemotherapy arm.
Duration of response
Median duration of response (months) in responding patients. The objective response rate was similar in both arms: 50.2% and 47.3%.
Although the proportion of patients whose tumors shrank was similar, responses lasted about twice as long in the sac-TMT + pembrolizumab arm.
Survival
Overall survival data are not yet mature; the median was not reached in either arm. In data presented only descriptively at the progression-free survival interim analysis, the trend is favorable: at 12 months, 77.6% of patients in the sac-TMT + pembrolizumab arm and 66.4% in the chemotherapy + pembrolizumab arm were alive. That is about 11 more patients out of every 100. The relative reduction in the risk of loss of life was 42% (HR 0.58; 95% CI 0.38–0.88). However, the number of events is small (36 vs 55), and this value should not be interpreted as a definitive result; the definitive answer will come with the final analysis.
Patients alive at 12 months
Overall survival rate (%), descriptive interim data. Colored bar: sac-TMT + pembrolizumab; grey bar: chemotherapy + pembrolizumab.
HR 0.58 (95% CI 0.38–0.88). Median follow-up 9.7 months; median overall survival was not reached in either arm. The data are immature.
Side effects
Grade ≥3 side effects were less frequent in the sac-TMT + pembrolizumab arm (47.6% vs 60.6%). The types of side effects, however, differ:
- Mouth sores (stomatitis): Common in the sac-TMT arm, but the vast majority are grade 1 or 2. They can be prevented and treated with oral care and, when needed, mouthwashes.
- Low blood counts: Can occur with both the conjugate and chemotherapy; regular blood counts are needed (leukopenia and neutropenia).
- Lung inflammation (pneumonitis): A side effect that can occur with both immunotherapy and antibody–drug conjugates and needs to be recognized early (antibody–drug conjugates and lung inflammation).
- Immune-related side effects: Because both arms included pembrolizumab, thyroid, bowel, liver and skin side effects can occur in either arm (immunotherapy side effects).
Serious side effects
Proportion of patients with grade ≥3 side effects (%).
Mouth sores (stomatitis) are common in the sac-TMT arm, but mostly grade 1 or 2.
Looking at it together with OptiTROP-Lung05
The same combination was also tested in PD-L1-positive patients. In OptiTROP-Lung05 (413 patients, China), published in the Lancet in May 2026, sac-TMT + pembrolizumab reduced the risk of progression by 65% compared with pembrolizumab alone (HR 0.35). However, the control arm in that trial was chemotherapy-free pembrolizumab, and grade ≥3 side effects were more frequent with the combination (55% vs 31%).
| Feature | OptiTROP-Lung05 | OptiTROP-Lung06 |
|---|---|---|
| PD-L1 status | Positive (1% or higher) | Negative (below 1%) |
| Number of patients | 413 | 455 |
| Control arm | Pembrolizumab alone | Chemotherapy + pembrolizumab |
| Progression-free survival | Not reached / 5.7 months (HR 0.35) | 15.0 / 5.7 months (HR 0.49) |
| Grade ≥3 side effects | 55% / 31% | 47.6% / 60.6% |
| Publication | Lancet, May 2026 | NEJM, October 2026 |
Because the patient populations and control arms of the two trials differ, the results cannot be compared directly.
How should the results be interpreted?
- Open-label design: Patients and physicians knew which treatment was being given; however, because the primary endpoint was assessed by an independent committee blinded to treatment, this limitation was partly offset.
- Conducted in China: The results need to be confirmed in patient populations in other countries, particularly in Western patients, among whom smoking rates are higher. MSD holds the rights to sac-TMT outside China, and global phase 3 trials are ongoing.
- Interim analysis and short follow-up: Median follow-up was 9.7 months. Whether the overall survival benefit will be durable is not yet known.
- Who was excluded: Patients with squamous histology, PD-L1-positive patients and those with targetable mutations were not enrolled (which is why next-generation sequencing is essential before treatment).
- Strong control arm: The fact that the trial was conducted against the most widely used standard treatment increases the value of the results.
Sacituzumab tirumotecan is not licensed in Turkey; nor is it yet approved in the US (FDA) or Europe (EMA). The drug is approved only in China, for four indications including EGFR-mutant lung cancer. In Turkey, the standard treatment for PD-L1-negative, non-squamous lung cancer without targetable mutations is platinum-pemetrexed chemotherapy + pembrolizumab; this combination is reimbursed by the SGK (Turkish Social Security Institution) for patients who meet its criteria (SGK reimbursement conditions for immunotherapy). For now, the way to access sac-TMT is through clinical trials. For access to new drugs, see our Turkey access map.
Advice for patients and their families
- Comprehensive molecular testing before treatment: Alterations such as EGFR, ALK, ROS1, KRAS, BRAF, MET, RET and HER2 can completely change treatment (HER2-mutant lung cancer, ALK-positive lung cancer).
- Know your PD-L1 result: Being PD-L1-negative does not mean immunotherapy will not work at all; immunotherapy combined with chemotherapy prolongs survival in this group as well. Dual immunotherapy is another option (nivolumab + ipilimumab).
- The standard has not changed for now: Sac-TMT is not available in Turkey; delaying treatment is not recommended. You can ask your doctor whether a suitable clinical trial is available.
- Oral care: For patients receiving an antibody–drug conjugate, a soft toothbrush, alcohol-free mouthwashes and telling the doctor as soon as a mouth sore appears are important.
- Report shortness of breath and cough: New or worsening shortness of breath, dry cough and fever can be early signs of lung inflammation.
- Stay active: Regular exercise during treatment reduces fatigue (rehabilitation and exercise in lung cancer).
For the symptoms and stages of lung cancer, see our general guide; for recent approvals, see our article on FDA approvals that changed lung cancer treatment in 2025; and for research on predicting response to immunotherapy, see our article on artificial intelligence and immunotherapy response. We have described the role of TROP2-directed drugs in breast cancer in our articles on sacituzumab govitecan and datopotamab deruxtecan.
Frequently asked questions
- What does PD-L1-negative lung cancer mean?
- It means that PD-L1 protein is detected on fewer than 1% of tumor cells. It occurs in about one third of non-small cell lung cancers. In these patients, immunotherapy alone is not enough; the standard treatment is a combination of chemotherapy + immunotherapy.
- What did the OptiTROP-Lung06 trial show?
- In PD-L1-negative advanced non-squamous lung cancer without targetable mutations, sacituzumab tirumotecan + pembrolizumab extended median progression-free survival from 5.7 to 15.0 months compared with chemotherapy + pembrolizumab (HR 0.49). Grade ≥3 side effects were less frequent; overall survival data are not yet mature.
- What is sacituzumab tirumotecan?
- An antibody–drug conjugate consisting of an antibody that binds to the TROP2 protein on the surface of tumor cells and an attached topoisomerase I inhibitor chemotherapy molecule. It was developed in China by Kelun-Biotech; MSD holds the rights outside China.
- Is sacituzumab tirumotecan available in Turkey?
- No. The drug is not licensed in Turkey, nor is it yet approved in the US or Europe. For now, access is possible only through clinical trials. In Turkey, the standard treatment is chemotherapy + pembrolizumab, reimbursed by the SGK for patients who meet its criteria.
Glossary
- PD-L1
- A protein that helps tumor cells hide from the immune system; its level is measured by the "tumor proportion score" (TPS).
- TROP2
- A protein found at high levels on the surface of many cancer cells; the target of antibody–drug conjugates.
- Antibody–drug conjugate (ADC)
- A drug consisting of an antibody that binds to a target and an attached potent chemotherapy molecule.
- Non-squamous non-small cell lung cancer
- Non-small cell lung cancers other than the squamous cell type, primarily adenocarcinoma.
- Progression-free survival
- The time from the start of treatment until disease progression or loss of life.
- Objective response rate
- The percentage of patients whose tumor shrinks by more than a defined amount.
- Open-label trial
- A trial in which patients and physicians know which treatment is being given.
- Stomatitis
- Inflammation and sores of the lining of the mouth.
DROZDOGAN Academy Commentary
OptiTROP-Lung06 is the first phase 3 evidence showing that replacing chemotherapy with an antibody–drug conjugate in PD-L1-negative lung cancer can be both more effective and better tolerated.
⚡ Why it matters
PD-L1-negative patients are the group that has benefited least in the immunotherapy era. The difference of about 9 months in median progression-free survival and the 28-point difference at 12 months are of a magnitude rarely seen in this field.
✅ Strengths
Randomized phase 3 design against a strong standard treatment, independent committee assessment, NEJM publication and fewer serious side effects. The doubling of the duration of response points to a durable effect.
⚠️ Limitations
Interim analysis, short follow-up, immature overall survival, open-label design and conduct in China only. Squamous histology was excluded.
🩺 In practice
For now, the standard in Turkey does not change; chemotherapy + immunotherapy continues. If sac-TMT is confirmed in global trials and approved, the choice of first-line treatment for PD-L1-negative patients could change substantially.
❓ Open questions
Will the overall survival benefit be confirmed? Will the same effect be seen in Western patients? How effective will chemotherapy be after progression? Will other TROP2 conjugates such as datopotamab deruxtecan produce similar results?
Bottom line: OptiTROP-Lung06 has put forward a strong candidate for chemotherapy-free first-line treatment in PD-L1-negative lung cancer. While overall survival data and global confirmation are awaited, chemotherapy + pembrolizumab remains the standard treatment in Turkey.
- This article was prepared in October 2026.
- The data were compiled from the abstract of the article published in NEJM, from the design, progression-free survival and overall survival slides of Prof. Caicun Zhou's ESMO 2026 presentation (LBA66) and from news reports based on company statements; the full text of the article was not accessed. Overall survival data were presented descriptively in the presentation.
- The detailed breakdown of side effects (for example, the rate of lung inflammation) is not included in this article.
- Information on licensing and reimbursement in Turkey reflects the date of writing and may change.
- This article is for general information only; it is not personal medical advice. The diagrams are derived from the text and contain no new data. The Academy commentary is our own.
References
- Zhou F, Meng X, Ding Q et al. Sacituzumab tirumotecan plus pembrolizumab in PD-L1–negative advanced NSCLC (OptiTROP-Lung06). N Engl J Med, October 25, 2026. doi:10.1056/NEJMoa2611280
- Zhou C. OptiTROP-Lung06: sacituzumab tirumotecan plus pembrolizumab vs chemotherapy plus pembrolizumab in PD-L1–negative advanced nsq-NSCLC. ESMO Congress 2026, LBA66, Madrid, October 25, 2026.
- Kelun-Biotech. Multiple sac-TMT studies selected as LBAs at ESMO 2026 (OptiTROP-Lung04 and OptiTROP-Lung06). September 22, 2026. placera.se
- Sac-TMT plus pembrolizumab beats chemo-immunotherapy in PD-L1–negative NSCLC. Targeted Oncology, July 15, 2026. targetedonc.com
- OptiTROP-Lung05: sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1–positive advanced NSCLC. Lancet 2026. doi:10.1016/S0140-6736(26)00968-2
- Gandhi L et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer (KEYNOTE-189). N Engl J Med 2018;378:2078-92. doi:10.1056/NEJMoa1801005
- Garassino MC et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol 2023;41:1992-8. doi:10.1200/JCO.22.01989
- Paz-Ares LG et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic NSCLC (EVOKE-01). J Clin Oncol 2024;42:2860-72. doi:10.1200/JCO.24.00733
- Ahn MJ et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic NSCLC (TROPION-Lung01). J Clin Oncol 2025;43:260-72. doi:10.1200/JCO-24-01544
- China NMPA approves sacituzumab tirumotecan for EGFR-mutant NSCLC. pharmashots.com
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