---
title: "SPIRAL-STONE: ICI plus bevacizumab-based chemotherapy in KRAS-mutant non-squamous NSCLC"
id: "frontiers-in-immunology-18-efficacy-and-safety-of-immune-checkpoint-inhibitor-plus-bevacizumab-based"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-efficacy-and-safety-of-immune-checkpoint-inhibitor-plus-bevacizumab-based"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1875501"
published_at: "2026-10-12T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SPIRAL-STONE: ICI plus bevacizumab-based chemotherapy in KRAS-mutant non-squamous NSCLC
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-efficacy-and-safety-of-immune-checkpoint-inhibitor-plus-bevacizumab-based
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1875501)
- **Published At:** 2026-10-12T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The SPIRAL-STONE study evaluated the combination of an **immune checkpoint inhibitor** plus **bevacizumab**-based chemotherapy in patients with advanced or recurrent **KRAS-mutant non-squamous NSCLC**. - The article title identifies the therapeutic combination and the molecular subgroup under study, specifying disease setting as advanced or recurrent. - The publicly available source content provided for this task did not include the study’s abstract, methods, numeric results, or safety tables; those details were not available in the supplied material. - The source did not report sample size, inclusion/exclusion criteria, treatment regimens or dosing, primary and secondary endpoints, statistical plan, or follow-up duration in the provided content. - The provided material did not include efficacy outcomes such as objective response rate, progression-free survival, overall survival, or duration of response. - Safety and tolerability data (treatment-emergent adverse events, immune-related adverse events, or bevacizumab-associated toxicities) were not present in the supplied text. - Biomarker analyses (PD-L1 expression, co-mutations, or KRAS subtype stratification) were not available in the provided content. - Regulatory status, practice guideline context, and next clinical steps were not reported in the accessible material. - Because the provided source content lacked core results and methods, clinicians should consult the full Frontiers in Immunology article or the journal site for complete data prior to applying findings to practice.
## Clinical Analysis & Structured Key Points
Frontiers | Efficacy and safety of immune checkpoint inhibitor plus bevacizumab-based chemotherapy in advanced or recurrent KRAS-mutant non-squamous NSCLC: the SPIRAL-STONE study ORIGINAL RESEARCH article Front. Immunol. , 12 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1875501 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by H M Hiromasa Morikawa Reviewed by L M Liyun Miao Y L Yaqi Liu R B Rafael Bugueno Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Baseline characteristics of the efficacy population (n = 21). View in article Table 2 Grade ≥3 treatment-related adverse events in the safety population (n=21). View in article ORIGINAL RESEARCH article Front. Immunol. , 12 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1875501 Efficacy and safety of immune checkpoint inhibitor plus bevacizumab-based chemotherapy in advanced or recurrent KRAS -mutant non-squamous NSCLC: the SPIRAL-STONE study M I Masaki Ishida 1 T Y Tadaaki Yamada 1 * R K Riko Kamada 2 M H Makoto Hibino 2,3 M E Masashi Egami 4 T N Takayuki Nakano 4 T I Tatsuya Imabayashi 5 C T Chieko Takumi 5 K I Koichi Ishida 6 M T Masafumi Takeshita 6 K M Ken Masubuchi 7 M I Miiru Izumi 8 T O Takayo Ota 9 S M Shoki Morito 10 Y C Yusuke Chihara 10 S H Soichi Hirai 11 S S Shinsuke Shiotsu 11 R S Ryo Sawada 1 H K Hayato Kawachi 1 N N Naoya Nishioka 1 M I Masahiro Iwasaku 1 +13 more K T Koichi Takayama 1 1. Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan 2. Department of Respiratory Medicine, Shonan Fujisawa Tokushukai Hospital, Kanagawa, Fujisawa, Japan 3. Department of Respiratory Medicine, Shonan Oiso Hospital, Kanagawa, Oiso, Japan 4. Department of Respiratory Medicine, Fukuchiyama City Hospital, Kyoto, Japan 5. Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan 6. Department of Respiratory Medicine, Ichinomiya Nishi Hospital, Aichi, Ichinomiya, Japan 7. Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Gunma, Japan 8. Department of Respiratory Medicine, National Hospital Organization Omuta National Hospital, Omuta, Fukuoka, Japan 9. Department of Breast Medical Oncology, Izumi City General Hospital, Izumi, Japan 10. Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Kyoto, Japan 11. Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan See more Article metrics View details Abstract Introduction: Kirsten rat sarcoma viral oncogene homolog ( KRAS )-mutant lung cancer is associated with a poor prognosis, underscoring the need for effective pharmacological treatments. An exploratory subgroup analysis of IMpower150 suggested potential clinical benefit of the atezolizumab-containing regimen in KRAS-mutant non-squamous NSCLC, although prospective data remain limited. We prospectively evaluated its efficacy and safety and performed exploratory biomarker analyses. Methods: The study cohort comprised patients with advanced or recurrent KRAS -mutant non-squamous NSCLC scheduled to receive ICI plus bevacizumab-based chemotherapy at 10 Japanese institutions between January 2023 and December 2024. The primary endpoint was progression-free survival (PFS). Secondary endpoints included disease control rate (DCR), objective response rate (ORR), overall survival (OS), and safety. Associations between baseline serum levels of vascular endothelial growth factor (VEGF)-A and VEGF-D and treatment outcomes were explored in patients with available pretreatment samples. Results: Of 22 enrolled patients, 21 received treatment and were analyzed for efficacy and safety; 17 were analyzed for serum biomarkers. All patients received atezolizumab, bevacizumab, carboplatin, and paclitaxel. The median PFS and OS were 6.0 and 17.1 months, respectively. Among 19 patients with measurable disease, the ORR was 42.1%, and the DCR was 68.4%. Grade ≥3 hematologic and non-hematologic adverse events occurred in 33.3% and 47.6% of patients, respectively. Baseline serum VEGF-A and VEGF-D levels were not significantly associated with the treatment outcomes. Conclusions: ICI plus bevacizumab-based chemotherapy showed an ORR of 42.1%, a median PFS of 6.0 months, and a median OS of 17.1 months in patients with KRAS -mutant non-squamous NSCLC. Given the small sample size and single-arm design, these findings should be considered descriptive and hypothesis-generating. Pretreatment serum VEGF-A and VEGF-D levels were not significantly associated with clinical outcomes, although limited statistical power precludes definitive conclusions. Larger comparative studies with comprehensive molecular profiling are warranted. 1 Introduction Pharmacotherapy for advanced non-small cell lung cancer (NSCLC) has substantially evolved with the advent of personalized medicine, including the discovery of oncogenic driver alterations, targeted therapies, and immune checkpoint inhibitors (ICIs), thereby improving patient prognosis ( 1 ). Among these, Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations are among the most common oncogenic driver alterations in NSCLC, occurring in approximately 25%–30% and 10%–15% of patients in Western and East Asian populations, respectively ( 2 – 4 ). KRAS -mutant NSCLC is increasingly recognized as a biologically and clinically heterogeneous disease rather than a single molecular entity ( 5 – 8 ). Its clinical characteristics and therapeutic sensitivity vary according to the specific KRAS mutation subtype and co-occurring genomic alterations, particularly those involving STK11 , KEAP1 , and TP53 . These molecular features are associated with distinct tumor immune microenvironments and may influence prognosis and responses to ICIs. The development of KRAS G12C inhibitors has expanded treatment options for patients with previously treated KRAS G12C-mutant NSCLC ( 9 , 10 ). However, KRAS G12C inhibitors are not currently established as standard first-line therapy, and effective targeted therapies remain limited for most non-G12C variants. In pivotal trials of patients with advanced non-squamous NSCLC without epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) alterations, the addition of an ICI to bevacizumab-based chemotherapy improved clinical outcomes compared with bevacizumab plus chemotherapy alone ( 11 , 12 ). However, the contemporary first-line treatment landscape for KRAS -mutant NSCLC includes several ICI-based strategies, and treatment selection is influenced by PD-L1 expression, patient characteristics, disease burden, KRAS mutation subtype, and co-occurring genomic alterations ( 5 , 7 , 8 ). An exploratory subgroup analysis of IMpower150 suggested that the atezolizumab-containing regimen may provide clinical benefit in patients with KRAS -mutant NSCLC ( 5 ). Nevertheless, these findings were derived from subgroup or indirect analyses and do not establish the superiority of this regimen over other first-line treatment options. Prospective data specifically evaluating the efficacy and safety of ICI plus bevacizumab-based chemotherapy in a molecularly defined KRAS -mutant population remain limited. Vascular endothelial growth factor (VEGF) signaling regulates both tumor angiogenesis and the immunosuppressive tumor microenvironment ( 13 ). Identifying biomarkers that predict response to anti-VEGF therapy combined with chemoimmunotherapy in NSCLC remains an important clinical challenge. Although circulating angiogenic factors, such as VEGF-A and VEGF-D, have been investigated as potential biomarkers for antiangiogenic therapy ( 14 , 15 ), their clinical relevance may vary depending on the antiangiogenic agent, treatment line, combination regimen, and patient population. In particular, it remains unclear whether pretreatment serum VEGF-A or VEGF-D levels are associated with clinical outcomes in patients with KRAS -mutant NSCLC treated with ICI plus bevacizumab-based chemotherapy. In this prospective multicenter study, we evaluated the efficacy and safety of ICI plus bevacizumab-based chemotherapy in patients with advanced or recurrent KRAS -mutant non-squamous NSCLC. We also performed an exploratory analysis to assess the correlation between pretreatment serum VEGF-A and VEGF-D levels and treatment outcomes in this molecularly defined population. 2 Material and methods 2.1 Study design and patients Patients diagnosed with advanced or recurrent KRAS -mutant non-squamous NSCLC who were scheduled to receive ICI plus bevacizumab-based chemotherapy at 10 institutions in Japan were prospectively enrolled between January 2023 and December 2024. All patients received atezolizumab plus bevacizumab, carboplatin, and paclitaxel (ABCP) as first-line systemic therapy for advanced or recurrent disease. None of the patients had received prior systemic anticancer therapy, including perioperative systemic therapy, or radiotherapy before initiation of the study treatment. The planned sample size was 30 patients, based on enrollment feasibility in routine clinical practice. No formal statistical power calculation was performed because this was an exploratory prospective observational study. The target sample size was therefore determined pragmatically rather than on the basis of a prespecified treatment effect or biomarker hypothesis. However, enrollment was closed at 22 patients because no additional eligible patients could be recruited during the predefined enrollment period. Patients were eligible if they met all of the following criteria: (1) a diagnosis of unresectable stage III, stage IV, or postoperative recurrent non-squamous NSCLC according to the American Joint Committee on Cancer Staging Manual, version 8, (2) age ≥20 years at the time of informed consent, (3) presence of a KRAS mutation, (4) planned treatment with an ICI plus bevacizumab-based chemotherapy, and (5) provision of written informed consent prior to study registration. Those with unresectable stage III disease were not candidates for definitive chemoradiotherapy. Patients harboring EGFR mutations or ALK rearrangements, as well as those deemed unsuitable for study participation by the treating physician after careful clinical review, were excluded. KRAS mutation status was determined using tumor tissue specimens by centralized molecular testing. An Oncomine-based assay was used in 15 patients, whereas an AmoyDx-based assay was used in the remaining six patients. Oncomine testing enabled identification of individual KRAS variants, whereas the AmoyDx assay reported certain variants, including G12A, G12V, G12R, and G13C, collectively as “ KRAS Others”. Therefore, the individual subtype could not be further specified for patients reported in this category. Other actionable driver alterations included in the respective assay panels were also evaluated, and no actionable alterations other than KRAS mutations were identified. STK11 , KEAP1 , and TP53 alterations were not assessed in this study. The data cutoff date was December 31, 2025. The median follow-up time was estimated using the reverse Kaplan–Meier method. Each patient’s medical record was prospectively reviewed. The following data were collected: age, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking status, tumor histology, disease stage, metastatic sites (bone, malignant pleural effusion [MPE], liver, and brain), KRAS mutation subtype, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), treatment regimens (induction and maintenance), treatment discontinuation and its reasons, subsequent systemic therapies, adverse events (AEs), and follow-up data, including treatment initiation, disease progression, death, and final follow-up. PD-L1 expression was assessed at SRL, Inc. using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Santa Clara, CA, USA), and TPS was recorded. AEs were graded according to the Common Terminology Criteria for Adverse Events version 5.0. The relationship between each AE and ABCP was assessed by the treating investigator. Clinical outcomes included the objective response rate (ORR), disease control rate (DCR), maximum percent change from baseline in the sum of target lesion diameters, progression-free survival (PFS), and overall survival (OS). Baseline laboratory values were collected to calculate the neutrophil-to-lymphocyte ratio (NLR), Glasgow Prognostic Score (GPS), and prognostic nutritional index (PNI). Baseline serum VEGF-A and VEGF-D levels were measured in patients with available pretreatment serum samples. The efficacy population comprised all patients who received at least one dose of ABCP, and PFS and OS were evaluated in this population. The safety population likewise comprised all patients who received at least one dose of ABCP. The response-evaluable population comprised patients in the efficacy population with measurable disease at baseline, in whom ORR and DCR were assessed. The biomarker population comprised patients in the efficacy population with available pretreatment serum samples. The primary endpoint was PFS in the efficacy population. Secondary endpoints included OS, ORR, DCR, and safety outcomes in the corresponding analysis populations described above. This study was conducted in accordance with the Declaration of Helsinki of the World Medical Association ( 16 ). The study protocol was approved by the Institutional Review Board of Kyoto Prefectural University of Medicine (ERB-C-2692-6) and each participating hospital and was registered at the University Hospital Medical Information Network (UMIN000049780; study information disclosed on January 4, 2023), before enrollment of the first patient. The manuscript was prepared in accordance with the STROBE reporting guideline for observational studies. All patients provided written informed consent before participation. 2.2 Treatment All patients received atezolizumab 1,200 mg/body, bevacizumab 15 mg/kg, carboplatin at an area under the curve of 6, and paclitaxel 200 mg/m² intravenously on day 1 of each 3-week cycle. Because this was an observational study, the number of induction cycles was not mandated by the study protocol and was determined by the treating physician in routine clinical practice. Four to six induction cycles could be administered according to the prescribing information and the patient’s clinical condition. Patients without disease progression or unacceptable toxicity could subsequently receive maintenance atezolizumab plus bevacizumab every 3 weeks. Treatment modification, interruption, or discontinuation was determined by the treating physician according to the prescribing information for each agent and the patient’s clinical condition. 2.3 Efficacy analysis PFS was defined as the time from initiation of ICI plus bevacizumab-based chemotherapy to the first documentation of radiologic or clinical disease progression or death from any cause, whichever occurred first. Patients without documented progression were censored at the last date on which they were confirmed to be progression-free. Treatment discontinuation or initiation of subsequent systemic therapy without documented progression did not constitute a PFS event or censoring event. OS was defined as the time from initiation of ICI plus bevacizumab-based chemotherapy to death from any cause. Tumor response was assessed by investigators at each institution in patients with measurable disease at baseline according to the Response Evaluation Criteria in Solid Tumors version 1.1. Because this was an observational study, the timing of radiologic assessments was not protocol-mandated; computed tomography or magnetic resonance imaging every 2–3 months was recommended during the observation period. The dates of individual response assessments were not prospectively captured in sufficient detail to reconstruct the actual imaging intervals reliably. Confirmatory imaging for complete or partial response was not required, and no minimum duration was prespecified for stable disease. The ORR was defined as the proportion of patients who achieved a complete or partial response as the best overall response. DCR was defined as the proportion of patients who achieved complete response, partial response, or stable disease. The maximum percentage change from baseline in the sum of the target lesion diameters was calculated among patients with measurable target lesions at baseline. 2.4 Assessments of serum VEGF-A and VEGF-D Baseline serum samples were prospectively collected before treatment initiation. Blood collection and serum processing were standardized across participating institutions. After collection, blood was allowed to clot at room temperature for 30 minutes and centrifuged at 1,000 × g for 15 minutes. The separated serum was aliquoted, frozen, and stored at −80 °C until analysis. The analyses of serum VEGF-A and VEGF-D were not prespecified in the study protocol and were conducted as exploratory biomarker analyses. VEGF-D was evaluated based on preclinical evidence suggesting that it may contribute to alternative angiogenic signaling when VEGF-A-mediated angiogenesis is inhibited ( 17 , 18 ). Because bevacizumab specifically neutralizes VEGF-A but does not directly inhibit VEGF-D, circulating VEGF-D was examined as an exploratory marker of VEGF-pathway activity outside the direct target spectrum of bevacizumab. Serum VEGF-A and VEGF-D concentrations were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. VEGF-A was measured using the Human VEGF-A ELISA Kit (RayBiotech, Peachtree Corners, GA, USA; catalog number ELH-VEGF), and VEGF-D was measured using the Human VEGF-D ELISA Kit (Aviva Systems Biology, San Diego, CA, USA; catalog number OKRC01017). Samples were measured in duplicate after two-fold dilution, and the mean of the duplicate measurements was used for analysis. All samples were analyzed in a single assay batch and underwent only one freeze–thaw cycle before measurement. All assays were performed according to the manufacturers’ instructions. According to the manufacturers’ specifications, the intra-assay and inter-assay coefficients of variation were <10% and <12%, respectively. All measured concentrations fell within the ranges of the standard curves used for quantification, and no samples required extrapolation beyond the standard curves. 2.5 Statistical analyses Statistical tests were two-sided, and statistical significance was set at p<0.05. Continuous variables are summarized as medians (ranges) and were compared using the Wilcoxon rank-sum test. Categorical variables were compared using the chi-square or Fisher exact test, as appropriate. The ORR and DCR were reported with 95% confidence intervals (CIs) estimated using the Wilson method. Baseline serum VEGF-A and VEGF-D levels were dichotomized using the sample median as the cutoff. The sample medians were 0.35 ng/mL for VEGF-A and 1.28 ng/mL for VEGF-D. Values equal to or above the sample median were classified as above-median, whereas values below the median were classified as below-median. As sensitivity analyses, baseline serum VEGF-A and VEGF-D levels were also evaluated as natural log-transformed continuous variables. Cox proportional hazards models were used to assess their associations with PFS and OS. Hazard ratios were expressed per doubling of the biomarker level and were calculated as exp[β × ln(2)], where β represents the Cox regression coefficient. Because of the limited sample size and number of outcome events, adjusted analyses included only smoking status as a potential confounder, and separate models were constructed for VEGF-A and VEGF-D to redu
## Related Clinical Research

- [53L10 T‑cell engager tribody for immunotherapy of multiple solid tumors — Frontiers in Immunology](https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-53l10-t-cell-engager-tribody-for-immunotherapy-of-multiple-solid-tumors.md)
- [Primary pulmonary MALT lymphoma presenting as a right hilar mass: CT and 18F-FDG PET/CT evaluation](https://medichelpline.com/clinical-feed/pubmed-42826325.md) (DOI: 10.1097/MD.0000000000051002)
- [Blood test trends versus single abnormal results to detect cancer in patients with unexpected weig](https://medichelpline.com/clinical-feed/plos-medicine-1-blood-test-trend-versus-single-threshold-abnormality-to-discriminate-cancer.md)
- [Chinese Medical Association 2026 Guideline: Clinical Diagnosis and Treatment of Lung Cancer](https://medichelpline.com/clinical-feed/pubmed-42764215.md) (DOI: 10.3760/cma.j.cn112152-20260511-00228)
- [MYC–MIZ1 Enhancer Complexes Regulate Neuroendocrine Identity in Small Cell Lung Cancer](https://medichelpline.com/clinical-feed/biorxiv-7-myc-miz1-complexes-at-enhancers-tune-neuroendocrine-identity-of-small-cell-lung.md)

## Navigation
- [← Back to Oncology Feed](https://medichelpline.com/clinical-feed/oncology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.