Combination metronomic chemotherapy and immunotherapy in non-small cell lung cancer remains exploratory: the VinMetAtezo trial

Introduction

Patients with advanced or metastatic non-small cell lung cancer (NSCLC) without molecular alterations for whom preferred first-line targeted therapies exist are typically treated with first-line platinum doublet chemotherapy with checkpoint inhibitor (CPI) immunotherapy against programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1), or just first-line CPI immunotherapy if the PD-L1 tumor proportion score (TPS) is ≥50%. In this setting, the population of patients who have not received first-line immunotherapy in theory is small, but may overrepresent those who are older, more ill, or more functionally limited by symptomatic brain metastases requiring corticosteroid therapy at initial diagnosis. Metronomic chemotherapy is an emerging treatment strategy in which low doses of anti-neoplastic agents are given in frequent intervals with limited drug-free breaks, typically with a more favorable side-effect profile. While an anti-angiogenesis mechanism was originally hypothesized for this strategy, more recent research suggests that metronomic chemotherapy may alter the tumor microenvironment and promote an antitumor immune response. Consequently, the combination of metronomic chemotherapy and CPI immunotherapy is a developing area of interest, of which the VinMetAtezo trial is a prime example (1).

Vinorelbine in NSCLC

Vinorelbine is a semi-synthetic vinca alkaloid which exerts its cytotoxic effects by binding to tubulin, inhibiting microtubule formation and leading to metaphase arrest. It was approved by the U.S. Food and Drug Administration (FDA) in 2000 as both a single-agent and in combination with cisplatin for first-line treatment of advanced, unresectable NSCLC, primarily based on a three-arm European multicenter trial comparing vinorelbine, vinorelbine plus cisplatin, and a related vinca alkaloid, vindesine, plus cisplatin. In this study, an objective response rate (ORR) of 30% and overall survival (OS) of 9.2 months was observed for the vinorelbine-cisplatin combination, compared to 14% ORR and 7.2 months OS for vinorelbine alone (2). An additional four-arm cooperative study in Japan demonstrated similar efficacy for the combination of cisplatin-vinorelbine compared to carboplatin-paclitaxel, in addition to the non-inferiority of two additional platinum-based regimens (cisplatin-irinotecan and cisplatin-gemcitabine) (3).

Despite these findings, vinorelbine is infrequently used in clinical practice, largely due to subsequent evidence of its inferiority compared to a newer chemotherapy agent from the taxane family, docetaxel. In a phase III trial of patients with advanced NSCLC who had previously failed platinum-containing regimens, single-agent docetaxel (at both 100 and 75 mg/m²) demonstrated superior ORR and progression-free survival (PFS) compared to single-agent vinorelbine, where ORR was only 1.1% (4). Subsequently, a large multi-national phase III trial of 1,218 patients showed that docetaxel-cisplatin was both more tolerable and more effective than vinorelbine-cisplatin in the first-line setting, specifically with regards to anemia, nausea, vomiting, and overall quality of life. While the third arm of this trial, docetaxel-carboplatin, was not superior to vinorelbine-cisplatin in terms of response and survival outcomes, it was also better tolerated, as expected (5).

Metronomic chemotherapy and the rationale to add immunotherapy

By itself, the term “metronomic” refers to something that is regular, periodic, and repetitive, as in a metronome used to keep tempo in music. When applied to chemotherapy, as coined by Hanahan et al., metronomic chemotherapy refers to chronic, relatively low-dose, minimally toxic regimens with no prolonged drug-free breaks (6). There is a preference for, but not requirement of, oral agents. By contrast, conventional chemotherapy regimens operate on a principle of administering treatment in cycles near the maximum tolerated dose (MTD) with drug-free periods in between to allow the patient to recover from drug-related side effects.

Metronomic chemotherapy was initially proposed to work via inhibition of tumor angiogenesis. The classic paradigm proposes a preferential effect upon tumor vasculature by effects on endothelial cell proliferation rather than direct tumor cell cytotoxicity, indirectly leading to tumor cell killing via induction of hypoxia and deprivation of nutrients (7). This theory was further supported by two landmark preclinical murine models by Klement et al. and Browder et al. as a way to overcome drug resistance (8,9). Yet more contemporary findings suggest that the mechanism of metronomic chemotherapy is likely multi-faceted, involving stimulation of the anti-cancer immune response, induction of tumor dormancy or senescence, and the so-called “4D effect” of drug-driven dependency/deprivation directly on tumor cells (10).

To date, metronomic chemotherapy is best studied in patients with advanced breast cancer, particularly with oral administration of drugs such as cyclophosphamide, methotrexate, and capecitabine. It has also been studied in multiple other solid tumors including ovarian cancer, castration-resistant prostate cancer, glioblastoma multiforme, and renal cell carcinoma, among others (11). Within advanced NSCLC, metronomic oral vinorelbine has been specifically investigated as a monotherapy in several small retrospective studies and phase II trials, with doses of 30–50 mg three times weekly, most often prescribed to elderly patients or those deemed unfit for conventional chemotherapy (12). Amongst four early-phase trials of single-agent metronomic oral vinorelbine, ORR ranged from 8.0% to 18.6%, with median time to progression between 2.2 and 5.0 months (13-16).

Given the proposed immunomodulatory mechanisms of metronomic chemotherapy, it is not surprising that its combination with CPI immunotherapy is an area of ongoing investigation. Underlying this is the fundamental question of whether metronomic chemotherapy can turn immunologically “cold” tumors “hot”, referring to tumors’ ability to provoke an immune response (characterized by factors such as degree of T-cell infiltration, neoantigen expression, and interferon-γ signaling), in turn increasing sensitivity to immunotherapy. In a preclinical syngeneic mouse model, He et al. demonstrated that metronomic chemotherapy plus an anti-PD-1 monoclonal antibody resulted in greater inhibition of squamous cell lung cancer growth than MTD chemotherapy plus the same anti-PD-1 monoclonal antibody. This enhanced effect was attributed to enhanced antigen exposure, improved antigen presentation by dendritic cells, and upregulation of PD-L1 expression in vivo (17). Clinically, an ongoing phase I/II multicenter basket study in France is evaluating the safety and efficacy of metronomic oral vinorelbine in combination with durvalumab (anti-PD-L1 monoclonal antibody) and tremelimumab [anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody] in advanced solid tumors (18). Furthermore, a parallel area of active study is the potential of metronomic chemotherapy to augment the activity of cancer vaccines (19,20).

The VinMetAtezo trial

VinMetAtezo was a multicenter, open-label, single-arm phase II trial assessing the safety and efficacy of second-line oral vinorelbine plus atezolizumab in patients with advanced NSCLC without activating epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations who had previously progressed on first-line platinum doublet chemotherapy (n=71). After a safety run-in phase involving the first twelve patients, treatment consisted of the anti-PD-L1 monoclonal antibody atezolizumab every three weeks and oral vinorelbine at a dose of 40 mg three times weekly, continued until radiographic disease progression. The primary endpoint of this study was PFS at four months. Secondary outcomes included median PFS, median OS, safety, ORR, and disease control rate (DCR). The median follow-up at time of analysis was 8.1 months (1).

In this single-arm trial, the authors based their efficacy thresholds on the phase III OAK study of single-agent atezolizumab versus docetaxel in the second- or third-line setting after platinum-based chemotherapy, where the 4-month PFS was 43% for the atezolizumab arm (21). The predefined 4-month PFS threshold in the VinMetAtezo trial to proceed to further phase III study was calculated to be 51% (or less than 35 progression or death events out of 71 patients).

The median age of the study population was 64 years, with a higher frequency of men (66.2%) than women. Most had former or current tobacco use (85.9%), ECOG performance status of 1 (62.0%), non-squamous histology (83.1%), and at least two sites of metastatic disease (73.2%). PD-L1 TPS was mostly <1% (52.9%) and 1–50% (42.6%), with few having high PD-L1 ≥50% (4.4%).

The 4-month PFS rate for the combination of metronomic oral vinorelbine plus atezolizumab was 32%, falling below the prespecified threshold for further phase III study. Median PFS and OS were 2.2 and 7.9 months, respectively. ORR and DCR at 4 months were 11% and 32%, respectively. There appears to be a tail of long-term survivors in the PFS curve of the PD-L1 1–50% subgroup that is not seen for the PD-L1 <1% subgroup, though the authors do not provide log-rank test P values for the difference between these survival curves. There were too few patients with PD-L1 ≥50% to make meaningful conclusions about this subgroup.

This regimen was overall well-tolerated, with 13.3% overall grade ≥3 adverse events (AEs) and only 5.1% grade ≥3 AEs attributed to study treatment. The most common serious AEs were GI side effects or cytopenias, namely diarrhea, vomiting, anemia, and neutropenia. Reasons for treatment discontinuation are not delineated, though a single grade 5 AE (death) was attributed to pneumonia.

Discussion and contextualization of VinMetAtezo

The VinMetAtezo trial was a negative study based on a single-stage phase II design, with prespecified thresholds for success and failure based on historical trial data. As the authors recognize, the ORR of 11% for the combination of metronomic oral vinorelbine and atezolizumab is numerically comparable to, but appears no better than that reported in the atezolizumab arm of the OAK study (14%). Of note, the VinMetAtezo trial did include a less fit patient population (9.9% versus not eligible, with ECOG performance status 2), fewer tumors with high PD-L1 TPS ≥50% (4.4% versus 17%), and lower proportion of tumors with squamous histology (16.9% versus 26%) compared to the OAK study (21). As other benchmarks of CPI immunotherapy in the second-line setting, KEYNOTE-010 demonstrated an ORR of 18% for pembrolizumab monotherapy (including only tumors with PD-L1 TPS ≥1%), while the ORR for nivolumab monotherapy in CheckMate 057 was 19% (across all PD-L1 levels) (22,23). Median PFS is comparable across these four trials, at 2.2 months (VinMetAtezo), 2.8 months (OAK), 3.9–4.0 months (KEYNOTE-010), and 2.3 months (CheckMate 057), respectively (21-23). These trials are further summarized in Table 1. The response and survival outcomes in VinMetAtezo are also numerically similar to historical data for single-agent metronomic oral vinorelbine (13-16).

Perhaps most importantly, since the publication of KEYNOTE-189 demonstrating improved PFS and OS with the addition of pembrolizumab to standard chemotherapy in treatment-naïve patients, CPI immunotherapy has moved firmly into the first-line setting in combination with platinum doublet chemotherapy, regardless of tumor PD-L1 expression (24). While it is true that some patients may not receive this standard-of-care due to temporary factors (e.g., symptomatic brain metastases requiring systemic corticosteroids at doses which may reduce efficacy of immunotherapy), this remains the minority of patients and others may have contraindications that are non-modifiable, such as prior autoimmune disease. Furthermore, even in those who do not receive immunotherapy in the first-line and are later considered for this therapy in the second-line setting, it is not clear based on the data from VinMetAtezo that adding metronomic vinorelbine is any better than single-agent CPI immunotherapy. Although it is challenging in a single-arm study, the proposed synergy between metronomic chemotherapy and CPI immunotherapy has not been clearly demonstrated here.

The safety and tolerability of this regimen is notable, with a rate of grade 3 or higher AEs less than half that of atezolizumab monotherapy in the OAK trial, and no new treatment emergent safety signals for this combination (21). Yet, while metronomic vinorelbine offers the convenience and perhaps lower cost of a tolerable oral therapy, its combination with an intravenous therapy, dosed once every three weeks, still ties the patient to the infusion center on a regular cadence (25).

The VinMetAtezo trial is an interesting study in that it addresses a few aspects in the management of advanced NSCLC not common in routine clinical practice—vinorelbine as a systemic agent, metronomic dosing of chemotherapy, and the combination of metronomic chemotherapy with immunotherapy. Based on existing evidence, single-agent metronomic vinorelbine, at least at current dosing strategies, has shown limited activity. Metronomic chemotherapy, even with other agents, has limited evidence base in NSCLC compared to other malignancies such as advanced breast cancer. While the immunomodulatory effects of a metronomic dosing strategy are proposed to prime the tumor microenvironment for CPI immunotherapy, it’s possible that an additional stimulus such as high PD-L1 or neoantigen expression is necessary for synergistic effect. The inclusion of additional patients with high PD-L1 expression or squamous histology could be considered, though the trial did already include a high proportion of patients with current or former smoking history. Lastly, the premise of this study, though not its results, raises the question of whether a combination metronomic chemotherapy and immunotherapy strategy could be effective in patients who have already progressed on other CPI immunotherapies.

Conclusions and future directions

Depending on PD-L1 status, the current standard-of-care first-line therapy for metastatic NSCLC without targetable driver alterations consists of CPI immunotherapy with or without platinum doublet chemotherapy. This has effectively superseded the use of PD-1 and PD-L1 inhibitors in the second-line setting. Currently, there is no evidence supporting the deferral of immunotherapy, except in situations where risk of toxicity is increased due to pre-existing conditions, or in molecular subtypes where limited efficacy of CPI immunotherapy has been demonstrated, as in EGFR, ALK, proto-oncogene tyrosine-protein kinase-1 (ROS1) and rearranged during transfection (RET)-altered NSCLC.

While the preclinical rationale for metronomic chemotherapy in combination with immunotherapy is worth further study, the VinMetAtezo trial does not provide evidence of this synergy. Yet the paradigm of metronomic chemotherapy remains attractive for its safety, tolerability, and patient convenience compared to the conventional strategy of MTD chemotherapy, particularly for older or less functional patients. Furthermore, based on the original understanding of metronomic chemotherapy’s effect on endothelial cells of the tumor vasculature, the addition of antiangiogenic drugs acting directly on vascular endothelial growth factor (VEGF), with or without immunotherapy, would be an interesting avenue of further exploration.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-53/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-53/coif). J.W.N. receives honoraria from CME Matter, Clinical Care Options, Research to Practice CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, and HMP Education; and consulting fees from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, and Anheart Therapeutics. J.W.N. also receives research funding from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen, AbbVie, and Novocure. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Vergnenegre A, Monnet I, Ricordel C, et al. Safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination in stage IV non-small-cell lung cancer: An open-label phase II trial (VinMetAtezo). Lung Cancer 2023;178:191-7. [Crossref] [PubMed]
2. Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994;12:360-7. [Crossref] [PubMed]
3. Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-23. [Crossref] [PubMed]
4. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354-62. [Crossref] [PubMed]
5. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016-24. [Crossref] [PubMed]
6. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045-7. [Crossref] [PubMed]
7. Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 1991;13:31-6. [Crossref] [PubMed]
8. Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15-24. [Crossref] [PubMed]
9. Browder T, Butterfield CE, Kräling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878-86. [PubMed]
10. Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 2010;7:455-65. [Crossref] [PubMed]
11. Simsek C, Esin E, Yalcin S. Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience. J Oncol 2019;2019:5483791. [Crossref] [PubMed]
12. Shu Y, Weng S, Zheng S. Metronomic chemotherapy in non-small cell lung cancer. Oncol Lett 2020;20:307. [Crossref] [PubMed]
13. Camerini A, Puccetti C, Donati S, et al. Metronomic oral vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer: results of a phase II trial (MOVE trial). BMC Cancer 2015;15:359. [Crossref] [PubMed]
14. Kontopodis E, Hatzidaki D, Varthalitis I, et al. A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group. J Chemother 2013;25:49-55. [Crossref] [PubMed]
15. Banna GL, Camerini A, Bronte G, et al. Oral Metronomic Vinorelbine in Advanced Non-small Cell Lung Cancer Patients Unfit for Chemotherapy. Anticancer Res 2018;38:3689-97. [Crossref] [PubMed]
16. Mencoboni M, Filiberti RA, Taveggia P, et al. Safety of First-line Chemotherapy with Metronomic Single-agent Oral Vinorelbine in Elderly Patients with NSCLC. Anticancer Res 2017;37:3189-94. [PubMed]
17. He X, Du Y, Wang Z, et al. Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma. J Immunother Cancer 2020;8:e000807. [Crossref] [PubMed]
18. Vicier C, Isambert N, Cropet C, et al. MOVIE: a phase I, open-label, multicenter study to evaluate the safety and tolerability of metronomic vinorelbine combined with durvalumab plus tremelimumab in patients with advanced solid tumors. ESMO Open 2022;7:100646. [Crossref] [PubMed]
19. Chen CA, Ho CM, Chang MC, et al. Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis. Mol Ther 2010;18:1233-43. [Crossref] [PubMed]
20. Ellebaek E, Engell-Noerregaard L, Iversen TZ, et al. Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother 2012;61:1791-804. [Crossref] [PubMed]
21. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65. [Crossref] [PubMed]
22. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-50. [Crossref] [PubMed]
23. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
24. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92. [Crossref] [PubMed]
25. André N, Banavali S, Snihur Y, et al. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013;14:e239-48. [Crossref] [PubMed]