Non-Squamous Lung Cancer: Anlotinib Maintenance After Benmelstobart Plus Chemotherapy
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Anlotinib After Benmelstobart + Chemotherapy: What Does the PFS Advantage Mean?
This Is Not Just “Another Immunotherapy” Study
The most important difference in TQB2450-III-11 is that the control arm is not a passive or weak treatment. In the control arm, tislelizumab, also a PD-1 inhibitor, was given with platinum-pemetrexed chemotherapy, followed by continued tislelizumab + pemetrexed maintenance. Thus, the experimental arm was tested against an active immunotherapy–chemotherapy standard rather than conventional chemotherapy.
The experimental strategy combines two axes: strengthening the antitumor immune response through PD-L1 blockade and suppressing tumor vasculature / angiogenesis signaling with anlotinib. The study therefore shows that treatment in non-squamous NSCLC can advance not only through PD-1/PD-L1 blockade but also through remodeling the tumor microenvironment and vascular biology .
Brief Concept Note: What Are Non-Squamous NSCLC, PD-L1, and Anti-Angiogenic Treatment?
Non-squamous NSCLCrefers to non-squamous subtypes of non-small cell lung cancer, particularly adenocarcinoma. PD-L1is a checkpoint protein that can help tumor cells evade the immune system. Anti-angiogenic treatmentis a treatment approach targeting a tumor’s capacity to form new blood vessels and its vascular microenvironment.
How Do Benmelstobart and Anlotinib Work?
Benmelstobartis a humanized IgG1 monoclonal antibody targeting PD-L1. By preventing PD-L1 from binding to PD-1, it aims to reduce suppression of T cells against the tumor and strengthen the antitumor immune response.
Anlotinib is an oral multitargeted tyrosine kinase inhibitor. It suppresses signaling pathways associated with blood vessel formation, tumor growth, and the tumor microenvironment, such as VEGFR, FGFR, PDGFR, and c-Kit. Adding anlotinib during maintenance therefore aims to suppress residual disease after chemotherapy and immunotherapy through vascular biology.
Benmelstobart + Chemotherapy Induction, Followed by Anlotinib-Containing Maintenance
TQB2450-III-11 is a randomized, open-label, parallel-controlled phase 3 study. It enrolled previously untreated patients with EGFR/ALK/ROS1 wild-type locally advanced or metastatic non-squamous NSCLC, comprising 596 patients .
In the experimental arm, patients received benmelstobart + carboplatin + pemetrexed induction, followed by benmelstobart + pemetrexed + anlotinib maintenance. In the control arm, tislelizumab + carboplatin + pemetrexed induction was followed by tislelizumab + pemetrexed maintenance. The primary endpoint was PFS assessed by an independent review committee.
| Treatment arm | Induction treatment | Maintenance treatment | Clinical rationale |
|---|---|---|---|
| Experimental arm | Benmelstobart + carboplatin + pemetrexed | Benmelstobart + pemetrexed + anlotinib | Targeting the tumor microenvironment with anti-angiogenic maintenance after PD-L1 blockade + chemotherapy. |
| Control arm | Tislelizumab + carboplatin + pemetrexed | Tislelizumab + pemetrexed | An active PD-1 inhibitor + chemotherapy and standard pemetrexed-containing maintenance approach. |
Brief Concept Note: What Do Induction and Maintenance Treatment Mean?
Induction treatmentis the more intensive phase given at the beginning of treatment to reduce tumor burden rapidly. Maintenance treatmentis treatment continued for longer after initial control has been achieved to delay renewed progression of the disease. In this study, anlotinib was added to treatment during the experimental arm’s maintenance period.
PFS: 14,42 Months Versus 8,34 Months
At approximately 9,7 months of median follow-up, the experimental arm achieved significant superiority for the primary endpoint, PFS. Median PFS in the anlotinib-containing maintenance arm after benmelstobart + chemotherapy was 14,42 months, compared with 8,34 months in the tislelizumab + chemotherapy arm. HR was 0,67 and the P value was 0,0017 .
This result indicates an approximately %33 relative reduction in the risk of progression or death with the experimental strategy. In addition, the 12-month PFS rate in the experimental arm was %57,6, compared with %43,2 in the control arm.
Brief Concept Note: How Should PFS and HR Be Interpreted?
PFSmeans progression-free survival; it represents how long the disease remains controlled without progression or death. HRmeans hazard ratio. An HR of 0,67 indicates that the risk of progression or death in the experimental arm is approximately %33 lower than in the control arm.
Clinical Significance of the PFS Result
- Benefit against an active control: The experimental arm demonstrated superiority against an active immunotherapy–chemotherapy regimen such as tislelizumab + chemotherapy, rather than a passive placebo.
- Importance of the maintenance period: Adding anlotinib during maintenance may be one of the main biological contributions to prolonging disease control.
- OS is not yet mature: A global-standard interpretation should not be made prematurely before the overall survival result becomes clear.
- Of interest in patients with low PD-L1: The persistence of the PFS advantage in PD-L1-negative/low groups may be clinically important.
A PFS Advantage Was Also Seen in PD-L1-Negative Patients
One notable aspect of the study was that the PFS advantage was generally maintained regardless of PD-L1 expression level. In patients with PD-L1 <%1, median PFS was 12,45 monthsin the experimental arm and 6,54 months in the control arm; HR was 0,61 .
In the PD-L1 %1–49 group, median PFS was 12,45 months versus 8,31 months, with an HR of 0,69 . In the PD-L1 ≥%50 group, median PFS was not reached in the experimental arm; median PFS in the control arm was 16,49 months ; HR was reported as 0,75 .
| PD-L1 level | Median PFS, experimental arm | Median PFS, control arm | HR | Clinical interpretation |
|---|---|---|---|---|
| PD-L1 <%1 | 12,45 months | 6,54 months | 0,61 | Supports the hypothesis that adding anti-angiogenic treatment may increase immunotherapy sensitivity in PD-L1-negative patients. |
| PD-L1 %1–49 | 12,45 months | 8,31 months | 0,69 | The PFS advantage is maintained in the low-to-intermediate PD-L1 group. |
| PD-L1 ≥%50 | Not reached | 16,49 months | 0,75 | There is also a trend favoring the experimental arm in the high PD-L1 group, but the control arm performs strongly as well. |
Brief Concept Note: Why Does the PD-L1 Level Matter?
PD-L1 expressionis one of the biomarkers used for immunotherapy selection and the probability of response. Patients with high PD-L1 may have a stronger response to immunotherapy; however, the efficacy of immunotherapy alone may be more limited in PD-L1-negative or low patients. Chemotherapy, anti-angiogenic treatment, or other combination strategies therefore become more important in low PD-L1 groups.
ORR Is Numerically Higher, and Response Duration Appears More Durable
The objective response rate was %51,3in the experimental arm and %45,3 in the control arm. Although this numerical difference favors the experimental arm, the study’s main distinguishing result is PFS and the durability of response rather than the response rate.
The 12-month duration-of-response rate was %66,0in the experimental arm, compared with %51,3 in the control arm. This finding suggests that the experimental strategy may not only initiate tumor shrinkage but also help maintain the response for longer.
Brief Concept Note: What Are ORR and DOR?
ORRmeans objective response rate; it indicates the proportion of patients whose tumors shrink measurably. DORmeans duration of response; it describes how long tumor shrinkage lasts. ORR indicates treatment’s ability to shrink the tumor, whereas DOR indicates the durability of that response.
Anti-Angiogenic Toxicities Are More Pronounced as Expected, With Similar Treatment Discontinuation
An overall expected pattern was observed between the two arms in the safety profile. In the safety table in the file you uploaded, the rate of any-grade treatment-related adverse effects was given as %99,3 in both arms. Rates of high-grade adverse effects of grade 3 and above were reported as %78,2in the experimental arm and %73,5 in the control arm. In the HMP Global summary, grade ≥3 treatment-related adverse event rates were reported in a lower category as %56,38 vs %48,66 . Thus, when interpreting the safety data, the distinction between adverse-effect categories and analysis sets needs attention.
Adverse effects associated with anlotinib and anti-angiogenic treatment, such as hypertension, proteinuria, and hypothyroidism, appear more pronounced in the experimental arm. In contrast, adverse-effect rates leading to treatment discontinuation were similar: %6,7in the experimental arm and %6,4in the control arm. The treatment-related death rate was reported as %1,7in the experimental arm and %2,4 in the control arm.
| Safety outcome | Experimental arm | Control arm | Clinical interpretation |
|---|---|---|---|
| Any-grade TRAE | %99,3 | %99,3 | Treatment-related adverse effects are very common in both arms. |
| Grade ≥3 high-grade adverse effects | %78,2 | %73,5 | High-grade events are frequent according to the table in the file you uploaded; external summaries report different adverse-effect categories with lower rates. |
| Serious adverse effects | %38,9 | %30,5 | Serious events are numerically more frequent in the experimental arm. |
| Adverse effects leading to treatment discontinuation | %6,7 | %6,4 | There appears to be no marked difference in permanent treatment discontinuation. |
| Treatment-related death | %1,7 | %2,4 | The death rate does not appear higher in the experimental arm; clinical monitoring nevertheless remains critical. |
Brief Concept Note: Why Do Proteinuria, Hypertension, and Hypothyroidism Occur?
Proteinuriais leakage of protein into urine and may occur with anti-angiogenic drugs targeting the VEGF/VEGFR pathway. Hypertensionis associated with suppression of vascular signaling pathways and is a common adverse effect of anti-angiogenic treatments. Hypothyroidismis reduced production of thyroid hormone; it may be associated with both immunotherapies and some tyrosine kinase inhibitors.
Practical Safety Note
With anlotinib-containing maintenance, blood pressure, urinary protein levels, thyroid function, liver tests, bleeding/thrombosis risk, and wound healing should be monitored carefully. Although this treatment strategy offers a PFS advantage, the benefit–risk balance must be individualized, particularly in older patients and those with hypertension, kidney disease, or a high risk of vascular events.
Anti-Angiogenic Treatment Is Not New in Lung Cancer, but It Is Seeking a New Position
The anti-angiogenic treatment approach is not new in non-squamous NSCLC. Bevacizumab with platinum-based chemotherapy has been an option used in some patients for many years. Ramucirumab has found a place mainly with docetaxel in the second line. However, the role of anti-angiogenic treatments is being redefined in the immunotherapy era.
The reason is that angiogenesis is associated not only with blood vessel formation but also with immune suppression in the tumor microenvironment. The VEGF axis can affect T-cell infiltration, dendritic cell function, hypoxia, and the intratumoral immune response. Combining anti-angiogenic treatment with immunotherapy is therefore biologically rational.
| Approach | Treatment rationale | Strength | Limitation | Relationship to TQB2450-III-11 |
|---|---|---|---|---|
| Chemotherapy + immunotherapy | Combination of PD-1/PD-L1 blockade and cytotoxic treatment | A standard approach in a broad patient population | Response may remain limited in patients with low/negative PD-L1 and immune resistance | The control arm is an active counterpart of this strong standard in Chinese practice. |
| Chemotherapy + anti-VEGF | Suppressing tumor vasculature and angiogenesis | Historical efficacy in non-squamous NSCLC | Hypertension, proteinuria, bleeding/thrombosis risk | Anlotinib brings this rationale into maintenance as an oral multitargeted TKI. |
| Immunotherapy + anti-angiogenic treatment | Jointly targeting the vascular and immune suppression axis in the tumor microenvironment | Potential to enhance the immune response | Toxicity and patient selection are more complex | Forms the biological foundation of the benmelstobart + anlotinib strategy. |
| Anlotinib maintenance after benmelstobart + chemotherapy | PD-L1 blockade, chemotherapy, and oral anti-angiogenic suppression during maintenance | PFS 14,42 vs 8,34 months; consistent benefit across PD-L1 subgroups | OS is not mature; global generalizability and toxicity management need clarification | Adds new phase 3 evidence for an immune–angiogenic maintenance strategy. |
The PFS Advantage Is Clear, but OS and Confirmatory Data Are Needed for a Global Standard
The TQB2450-III-11 study shows that an anlotinib-containing maintenance strategy following first-line benmelstobart + chemotherapy can significantly prolong disease control in non-squamous NSCLC. The preservation of benefit particularly in PD-L1-negative and low-to-intermediate expression patients suggests this strategy may be valuable in patient groups with potentially limited immunotherapy sensitivity.
Nevertheless, it may be too early to interpret this approach as a global standard. Overall survival data are immature. Factors such as the study population, the control agent used, geographic context, access to drugs, and management of anti-angiogenic toxicity may also affect the applicability of treatment in different countries.
Practical Lessons That Can Be Drawn Today
- Driver mutation testing is essential: Such immunotherapy–chemotherapy strategies should not be planned without confirming EGFR/ALK/ROS1 wild-type status.
- PD-L1-negative patients matter: The PFS difference in the PD-L1 <%1 group suggests a biological contribution from adding anti-angiogenic treatment.
- Maintenance treatment is a new area of competition: The maintenance strategy can determine the duration of disease control as much as the initial induction.
- Anti-angiogenic toxicity should be monitored: Hypertension, proteinuria, bleeding/thrombosis, and thyroid function should be followed.
- OS should be awaited: Although PFS is positive, the treatment’s ultimate clinical significance will be clarified by overall survival and quality-of-life data.
How Should We Talk to the Patient?
“In this study, after starting treatment for lung cancer with a drug that strengthens the immune system and chemotherapy, an oral drug targeting tumor blood vessels was added during maintenance. This approach prolonged the period during which the disease remained controlled without progressing. However, its effect on life expectancy is not yet fully clear, and regular monitoring is needed for adverse effects such as high blood pressure, protein leakage in urine, and thyroid problems.”
Maintenance Strategies Targeting the Tumor Microenvironment Are Coming to the Fore
Academic Assessment
This study provides important ASCO 2026 evidence showing that adding anti-angiogenic suppression to immunotherapy and chemotherapy can significantly prolong disease control in non-squamous lung cancer.
The PFS advantage independent of PD-L1 level is notable in terms of the potential of intervening in the tumor microenvironment, particularly to enhance the immunotherapy response.
The true place of such combinations in the future will become clearer through overall survival results, toxicity management, and biomarkers determining which patients will benefit most.
Which Data Will Determine the True Place of This Strategy?
TQB2450-III-11 presented a strong and statistically significant PFS result. However, lasting changes in clinical practice require OS, quality-of-life, toxicity-management, biomarker, and confirmatory data in different populations.
Open Questions
- Overall survival: Will the PFS advantage translate into an OS advantage?
- The most suitable patient group: Do PD-L1-negative or low-expression patients benefit more from this strategy?
- Biomarkers: Can a VEGF/angiogenesis signature, the tumor microenvironment, TMB, or immune infiltration improve patient selection?
- Toxicity management: How will anti-angiogenic adverse effects affect treatment continuity in real-world practice?
- The control standard: How will the strategy be positioned against pembrolizumab-, atezolizumab-, sintilimab-, or tislelizumab-based regimens used in different countries?
- Maintenance duration: How long should anlotinib maintenance continue, and in which patients can it be stopped early?
Truecheck Note
This is a positive phase 3 study for PFS, but OS data are not yet mature. In addition, safety rates are reported using different adverse-effect categories across sources. Thus, when interpreting the treatment’s clinical value, the PFS gain, anti-angiogenic toxicity burden, treatment discontinuation rate, and mature OS data should be assessed together.
Anlotinib After Benmelstobart + Chemotherapy Reopens the Debate on Maintenance Treatment in Non-Squamous NSCLC
The TQB2450-III-11 phase 3 study presented at ASCO 2026 showed that an anlotinib-containing maintenance strategy after benmelstobart + chemotherapy significantly prolonged PFS compared with tislelizumab + pemetrexed maintenance after tislelizumab + chemotherapy in EGFR/ALK/ROS1 wild-type locally advanced or metastatic non-squamous NSCLC. Median PFS was reported as 14,42 months versus 8,34 months, with HR 0,67 and P=0,0017.
The preservation of the PFS advantage in PD-L1-negative and low-to-intermediate expression groups suggests that anti-angiogenic treatment may create a microenvironment effect capable of enhancing the immunotherapy response. While the response rate numerically favored the experimental arm, the higher 12-month duration-of-response rate indicates that responses may be more durable.
In contrast, positioning this approach as a new global standard before overall survival data mature would be premature. Hypertension, proteinuria, and other anti-angiogenic toxicities associated with anlotinib require careful monitoring in practice. Nevertheless, this study shows that first-line treatment in non-squamous NSCLC is no longer solely chemotherapy and PD-1/PD-L1 blockade; maintenance strategies targeting tumor vascular biology and the microenvironment are becoming increasingly important.
References
- ASCO 2026 LBA8507. A randomized, open-label, parallel-controlled phase 3 trial of benmelstobart plus chemotherapy and anlotinib for first-line treatment of advanced non-squamous NSCLC.
- HMP Global Learning Network. Benmelstobart Plus Anlotinib as Potential New First-Line Option in Advanced NSCLC. 2026.
- National Cancer Institute Drug Dictionary. Benmelstobart definition.
- CenterWatch. NCT05346952: TQB2450 plus chemotherapy followed by TQB2450 plus anlotinib versus tislelizumab plus chemotherapy in first-line non-squamous NSCLC.
- The ASCO Post. Benmelstobart Plus Anlotinib in First-Line Treatment for PD-L1–Positive Advanced NSCLC. 2026.
- Cheng P et al. Benmelstobart + anlotinib: an emerging therapeutic option in oncology. Frontiers in Oncology. 2026.
- drozdogan.com. Triple Combination in Small Cell Lung Cancer: The Best Results Obtained So Far. 2023.
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