Single-Arm 18% Response Without Precedent Faces Phase 3 and Payer Reckoning

Marengo's Bispecific Antibody Shows Broad Efficacy in Multiple Cancers

Marengo Therapeutics announced positive Phase 1/2 results for its first-in-class bispecific antibody, invikafusp alfa, from the Start-001 study at ESMO 2026. The drug demonstrated objective responses across eight tumor types, including breast, colorectal, and non-small cell lung cancers, particularly in patients who had not responded to previous checkpoint inhibitor therapy. The study showed tumor shrinkage in 56% of patients, an 18% objective response rate, and a 60% disease control rate across all patients. Invikafusp alfa, a selective T cell agonist, activates Vβ T cells to enhance antitumor immune responses, extending immunotherapy beyond traditional checkpoint blockade. The company holds two FDA Fast Track designations and plans late-stage development in 2027.

• Invikafusp alfa demonstrated significant efficacy in a heavily pretreated patient population, including those unresponsive to prior immune checkpoint blockade. The Phase 1/2 Start-001 study reported an 18% objective response rate and a 60% disease control rate across all 62 patients, with tumor shrinkage observed in 56%. Notably, patients previously treated with immune checkpoint inhibitors showed a 20% ORR and 68% DCR, surpassing those who were treatment-naïve.
• The drug's unique mechanism of action as a selective Vβ T cell agonist differentiates it from existing immunotherapies. By activating and expanding a naturally occurring group of T cells, invikafusp alfa aims to overcome the limitations of checkpoint inhibitors, which often fail when responsive T cells are scarce or dysfunctional. This approach has shown tissue-agnostic efficacy, proving effective in both 'cold' cancers like colorectal and 'hot' cancers such as non-small cell lung cancer.
• Marengo Therapeutics has secured two FDA Fast Track designations for invikafusp alfa, underscoring its potential to address unmet needs in oncology. The company plans to advance the candidate into late-stage development in 2027. Additionally, early results from a separate Phase 2 study (Start-002) combining invikafusp alfa with Gilead Sciences’ Trodelvy in metastatic breast cancer patients have shown promising complete responses.

Addressing Unmet Needs in Immunotherapy-Resistant Cancers

Recent development in solid tumors centers on populations with limited responsiveness to immune checkpoint inhibitors, refractory heavily pretreated disease, and molecularly defined subsets lacking effective options. Resistance mediated by an inherently immunosuppressive tumor microenvironment and immune-related adverse events remain major challenges across non-small cell lung cancer, small cell lung cancer and pancreatic cancer.

• Non-small cell lung cancer and small cell lung cancer with immunotherapy resistance: Lung cancer remains a significant contributor to cancer mortality as a molecularly heterogeneous disease with dramatic resistance mediated by an inherently immunosuppressive tumor microenvironment. Immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 drive treatment, including Nivolumab, Pembrolizumab, Durvalumab, and emerging bispecific combinations, with predictive biomarkers including PD-L1 expression, tumor mutational burden, circulating tumor DNA, and radiomic features used to select patients.

• Microsatellite stable and mismatch repair-proficient colorectal cancer refractory to standard therapy: Most advanced colorectal cancer patients with proficient DNA mismatch repair or microsatellite stability are insensitive to immune checkpoint inhibitor therapy. Populations studied include heavily pretreated refractory colon adenocarcinoma with microsatellite stability treated with sintilimab, bevacizumab and chemotherapy with progression-free survival of approximately 9.3 months and overall survival of approximately 57 months, and chemotherapy-refractory metastatic colorectal cancer in FRESCO-2 with median overall survival of 7·4 months in the fruquintinib group versus 4·8 months in the placebo group.

• CLDN18.2-positive gastric, gastroesophageal, pancreatic and other solid tumors: Patients with gastric and pancreatic cancers, as well as ovarian, lung, liver, and colon cancers, often lack effective therapeutic options. Claudin 18.2 is predominantly expressed in gastric and pancreatic cancers and found in other tumor types, targeted by zolbetuximab added to chemotherapy in first-line advanced gastroesophageal adenocarcinomas with ≥ 75% CLDN18.2 expression, and by antibody-drug conjugates LM-302 and IBI343, bispecific anti-CLDN18.2/CD3 antibody IBI38, chimeric antigen receptor T cell therapy satricabtagene autoleucel, SOT102, FG-M108, and AHT-102.

• Pancreatic ductal adenocarcinoma with dense immunosuppressive microenvironment and biomarker-defined subsets: Pancreatic ductal adenocarcinoma has a 5-year survival rate of less than 10% with dense, immunosuppressive tumor microenvironment limiting conventional therapies and CLDN18.2-targeted CAR-T therapy. Biomarker-defined subsets include KRAS G12C targeted by adagrasib, mismatch repair deficiency or high microsatellite instability treated with dostarlimab, and HER2-positive disease treated with trastuzumab deruxtecan.

• Heavily pretreated metastatic melanoma after anti-PD-1 failure and metastatic breast cancer: Nivolumab plus ipilimumab administered in third line or beyond after at least two prior lines showed overall response rate of 23.3%, median duration of response of 19.4 months, median PFS of 2.7 months and median OS of 9.6 months, with reduced efficacy after prior anti-CTLA-4 exposure. Metastatic breast cancer treated with immune checkpoint inhibitor-based therapy showed overall objective response rate of 36.7%, disease control rate of 78.9%, median PFS of 4.9 months and median OS of 13.9 months, with triple negative in 53.3% and heavily pretreated lines ≥3 in 61.1%.

• Elderly advanced non-small cell lung cancer and central nervous system involvement: Elderly patients aged ≥70 years with stage III-IV non-small cell lung cancer with negative driver gene mutations and comorbidities limiting standard chemotherapy were treated with drug-eluting bead bronchial arterial chemoembolisation combined with immunotherapy with median progression-free survival of 9.1 months and overall survival of 18.2 months. Lung cancer patients with suspected leptomeningeal disease showed cerebrospinal fluid tumor-derived DNA variant allele fractions with median of 32.7% versus plasma circulating tumor DNA of 1.8%, with cytology 81.8% sensitive and CSF-tDNA 91.7% sensitive for diagnosis.

Invikafusp Alfa's Phase 2 Efficacy Across Diverse Solid Tumors

This first-in-human, Phase 1/2a, open-label study (NCT05397171) assessed AZD8853 monotherapy, an anti-GDF15 monoclonal antibody, in previously treated patients with advanced/metastatic microsatellite-stable colorectal cancer (MSS-CRC) and urothelial carcinoma (UC). During dose escalation, 16 patients received AZD8853 300 mg (n=3), 1000 mg (n=6), or 3000 mg (n=7) IV every 3 weeks (Q3W); 15 had MSS-CRC and 1 had UC. AZD8853 showed linear pharmacokinetics with a half-life of 5-10 days, supporting Q3W dosing, while AZD8853 suppression of GDF15 was transient with no evidence of ctDNA clearance or dose-dependent changes in peripheral T cells. The best response per RECIST v1.1 was stable disease in 5 patients (31.3%) and disease progression in 11 patients (68.8%), and the study was stopped after dose escalation. For safety, 13 patients (81.3%) had treatment-emergent adverse events (TEAE), most commonly diarrhea (31.3%), abdominal pain (31.3%) and decreased appetite (25%), with 8 patients (50.0%) having grade ≥3 TEAEs and 6 (37.5%) having serious TEAEs, none treatment-related, and there were no DLTs.

AdvanTIG-105 was a phase I, first-in-human, dose escalation study (NCT04047862) evaluating ociperlimab, a humanized monoclonal antibody binding to T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT), in combination with tislelizumab 200 mg, an anti-programmed cell death protein 1 mAb, in patients with advanced solid tumors previously treated with standard systemic therapy. At data cut-off (September 29, 2022), 32 patients had received ≥1 dose of ociperlimab plus tislelizumab 200 mg Q3W across ociperlimab dose levels of 50 mg, 150 mg, 450 mg, 900 mg and 1800 mg, with a median age of 59.5 years (range: 31-79). Preliminary antitumor activity was observed with 450 mg, 900 mg, and 1800 mg ociperlimab, with overall response rate (ORR) of 10.0%, median duration of response (DoR) of 3.6 months, and disease control rate (DCR) of 50.0% per Response Evaluation Criteria in Solid Tumors version 1.1. The combination was well tolerated, with 96.9% experiencing ≥1 treatment-emergent adverse event (TEAE), 62.5% experiencing ≥grade 3 TEAEs and 50.0% experiencing serious TEAEs, with no dose limiting toxicity events reported, maximum tolerated dose not reached, and recommended phase II dose (RP2D) of ociperlimab 900 mg plus tislelizumab 200 mg Q3W.

This open-label, single-arm, phase 2 study (NCT03667170) evaluated weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, in previously treated advanced defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors from 25 clinical sites across China. One hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled with median follow-up of 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0-52.8), and the disease control rate was 66.0% (95% CI 56.0-75.1), with median duration of response not reached and duration of response rate at 12 months of 92.2% (95% CI 77.5-97.4), median progression-free survival of 11.1 months (95% CI 5.5 to not evaluable), and overall survival at 12 months of 74.6% (95% CI 64.7-82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event with no grade 5 treatment-emergent adverse events related to envafolimab reported, injection site reactions, all grade 1-2, were reported in nine patients (9%) with no infusion reactions, and 8 patients (8%) had grade 3 or 4 immune-related adverse events.

Invikafusp Alfa: A Precision Immunotherapy Backbone for Combinations

Antibody-drug conjugate (ADC) plus immune checkpoint inhibitor (ICI) combinations are being systematically evaluated as synergistic partners across solid malignancies. ADCs enhance ICI efficacy by inducing immunogenic cell death, which activates tumor-specific immune responses, remodeling the immunosuppressive tumor microenvironment, and amplifying ICI-mediated immune cell activation. The review reports encouraging antitumor activity for ADC-ICI combinations across multiple types of solid malignancies, with ongoing research focused on new ADC structures, including multispecific antibodies and noncytotoxic payloads, and diverse combination approaches.

Poly (ADP-ribose) polymerase (PARP) inhibitor plus ICI combinations represent a rational strategy grounded in DNA damage response deficiencies and genomic instability. PARP inhibitor-mediated unrepaired DNA damages modulate the tumor immune microenvironment by increasing genomic instability, immune pathway activation, and PD-L1 expression on cancer cells, which might promote responsiveness to ICIs such as anti-PD1/PD-L1 and anti-CTLA-4. In parallel, co-targeting of epigenetic regulators and BCL-XL is being investigated to sensitize solid tumors to immune checkpoint blockade (ICB). Treatment with epigenetic drugs targeting DNA methyltransferase, histone methyltransferase, and histone deacetylase enzymes in combination with a BCL-XL inhibitor resulted in marked synergistic in vitro responses in human and mouse solid tumor cell lines, with induction of endogenous retroelements that led to immunogenic cell death. A triple combination of epigenetic and BCL-XL inhibitors with an anti-PD-1 monoclonal antibody reduced tumor growth and prolonged overall survival in murine syngeneic and orthotopic models of lung, colorectal and breast carcinomas, melanoma, and glioblastoma, associated with expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes.

ICI-based combinations have evolved from single-agent blockade of CTLA-4, PD-1 and PD-L1 to combination of anti CTLA-4 and PD-1, and immune checkpoint blockade combined with chemotherapy, anti-angiogenic agents and kinase inhibitors to heighten potency and duration of immune responses. A phase I/Ib study (NCT01988896) treated PD-L1/PD-1-naive patients with solid tumors with cobimetinib dosed once daily orally for 21 days on, 7 days off plus atezolizumab dosed at 800 mg intravenously every 2 weeks; among 150 patients who received ≥1 dose, including metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16), confirmed responses were observed in 7 of 84 patients (8%) with mCRC, 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC, with clinical activity independent of KRAS/BRAF status. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise with several trials ongoing in metastatic melanoma, while a PD-L1 binding peptide conjugate nanoparticle with tumor extracellular pH-responsiveness loaded with doxorubicin (DOX@DCS NPs) showed efficient inhibition of CT26 tumors by blocking PD-1/PD-L1 and inducing immunogenic cell death of cancer cells.

Marengo's Invikafusp Alfa: Reshaping Immunotherapy for CPI-Failed Patients

The recent announcement from Marengo Therapeutics regarding positive Phase 1/2 results for invikafusp alfa at ESMO 2026 signals a potentially transformative moment in immuno-oncology. This first-in-class bispecific antibody, designed to selectively activate Vβ T cells, represents a novel mechanism that extends the reach of immunotherapy beyond traditional checkpoint blockade. The data, showing objective responses across eight diverse tumor types, including breast, colorectal, and non-small cell lung cancers, are particularly compelling as they were observed in patients who had previously failed checkpoint inhibitor therapy. This addresses a significant unmet medical need, offering a new therapeutic avenue for individuals with limited treatment options.

Strategically, Marengo is positioning invikafusp alfa to capture a crucial segment of the refractory cancer market. Its broad activity across multiple tumor types suggests a potential for a pan-cancer approach, which could significantly expand its market footprint and reduce development risks associated with single-indication drugs. The two FDA Fast Track designations further underscore the regulatory recognition of its potential, hinting at an accelerated path to market and the establishment of a new class of immuno-oncology agents.

However, as with all early-stage data, important considerations remain. While the 18% objective response rate and 60% disease control rate are encouraging for a heavily pre-treated population, the full efficacy and safety profile will need to be rigorously validated in larger, late-stage clinical trials. The long-term safety and durability of response for this novel Vβ T cell activation mechanism are yet to be fully characterized, and potential unforeseen immune-related adverse events or resistance mechanisms could emerge. Furthermore, the ultimate clinical utility will depend on demonstrating a compelling advantage over existing or emerging therapies in head-to-head comparisons. As Marengo plans late-stage development in 2027, the oncology community will keenly watch how invikafusp alfa navigates these challenges, potentially ushering in a new era of T cell-directed immunotherapies.