Combination Immunotherapy and TKI Strategies in ACC

Immunotherapy

Combination immunotherapy and tyrosine kinase inhibitor (TKI) strategies in adrenocortical carcinoma (ACC) are investigational systemic approaches for advanced disease, particularly recurrent, unresectable, or metastatic ACC after standard local therapy is no longer feasible.¹² In current ACC care, they sit within later-line or trial-based medical management rather than replacing surgery, mitotane-based treatment, or cytotoxic chemotherapy for most patients.¹² The main combination approaches include dual immune checkpoint blockade, usually PD-1 plus CTLA-4 inhibition, and checkpoint inhibitor regimens paired with antiangiogenic or multikinase TKIs.¹³

Interest in these combinations reflects the limited activity of single-agent checkpoint inhibition in unselected ACC, alongside biologic signals that a minority of tumors may remain immunologically targetable.¹² Potential rationale includes broader immune activation with dual checkpoint blockade and microenvironmental modulation with TKIs, particularly where angiogenic, stromal, or endocrine factors may contribute to immune resistance.¹⁴ The clearest currently recognized responsive subgroup is the mismatch repair-deficient or microsatellite-instability-high subset, which represents only a minority of ACC cases.⁵¹

The evidence base remains limited and is dominated by small prospective cohorts, basket studies, retrospective synthesis, and review literature rather than ACC-specific randomized comparisons.²³ Available data suggest that durable responses may occur in selected patients, but average response rates and progression-free survival remain modest, and a population-level advantage over monotherapy or established systemic options has not been demonstrated.⁵² This makes patient selection and treatment context more important than the nominal use of combination therapy alone.

Diagnostic and Biological Context

ACC has several features that make checkpoint-based combination therapy biologically plausible but clinically inconsistent. A minority of tumors show mismatch repair deficiency or MSI-H status, which appears to enrich for benefit from checkpoint inhibition, while many other ACCs appear to have an immunologically unfavorable microenvironment with limited effective antitumor infiltration.⁵¹⁴ Hormone secretion is also relevant, because glucocorticoid excess may suppress antitumor immunity and contribute to resistance.¹³

This biologic heterogeneity helps explain why combination strategies have been pursued. The relatively reliable conclusion is that resistance in ACC is multifactorial and not fully captured by any single marker.¹⁴ The less reliable assumption is that adding a second immune or targeted agent will broadly overcome resistance across unselected ACC. Clinically, this favors biomarker-aware use and trial enrollment over empiric routine escalation.

Major Therapeutic Approaches

Dual Checkpoint Blockade

Dual checkpoint blockade with PD-1 and CTLA-4 inhibition is the best described immunotherapy combination strategy in ACC.⁵¹ Limited ACC-specific experience suggests that objective responses can occur and may be durable in rare cases, but the signal appears concentrated in biologically selected tumors, particularly MSI-H disease, rather than evenly distributed across advanced ACC as a whole.⁵

The most reliable interpretation is that dual checkpoint blockade has real but narrow activity in ACC.⁵² What remains uncertain is whether it improves expected outcomes for the overall ACC population, because the available cohorts are very small and nonrandomized. In practice, this supports selective use in biomarker-enriched settings or within clinical trials rather than broad adoption for all patients with metastatic disease.

Checkpoint Inhibitor Plus TKI

Checkpoint inhibitor plus TKI combinations are intended to pair immune activation with effects on angiogenesis, stromal structure, and immune-cell trafficking.¹⁴ In ACC, this strategy is attractive because the tumor microenvironment may include vascular and immunosuppressive features that limit response to checkpoint therapy alone.¹⁴ Early prospective evidence indicates that such regimens are feasible and can produce disease control in some patients, but objective responses have been uncommon and median progression-free survival has remained short.²³

The dependable message is that checkpoint-TKI combinations may benefit a minority of selected patients.²³ The less dependable inference is that they are clearly superior to checkpoint monotherapy, mitotane-based treatment, or other later-line approaches, because current evidence does not establish a consistent comparative advantage. Their present role therefore remains mainly investigational.

Patterns of Benefit and Patient Selection

Across the broader checkpoint literature in advanced ACC, efficacy remains modest at the population level. Pooled data show low objective response rates, moderate disease control rates, and short median progression-free survival, without clear evidence that combination regimens consistently outperform monotherapy in unselected patients.² This overall pattern is more compatible with occasional meaningful benefit in selected subgroups than with a general change in expected outcomes for advanced ACC.

Patient selection is therefore central to the practical use of these regimens. Mismatch repair deficiency and MSI-H status are the most established markers associated with greater likelihood of response to checkpoint-based therapy.⁵¹ By contrast, hormonally active disease associated with glucocorticoid excess may identify a less responsive phenotype; in prospective combination data, patients with ACC and Cushing syndrome did not show objective responses.³

Emerging translational work also supports marked microenvironmental heterogeneity within ACC. Bioinformatic analyses suggest that some tumors have immunosuppressive states characterized by reduced cytotoxic immune infiltrates and increased regulatory or exhausted immune signatures, which may help explain resistance even when checkpoint targets are expressed.⁴ The reliable implication is that tumor biology matters substantially; the unreliable shortcut is to use any single biomarker as a sufficient standalone treatment selector. Clinically, integrated assessment of molecular features, hormone status, disease tempo, and prior therapy is likely more informative than choosing combination therapy on mechanism alone.

Toxicity and Practical Pitfalls

Because average efficacy is limited, toxicity has a major effect on the net value of combination therapy in ACC. Dual checkpoint blockade may increase immune-related toxicity compared with single-agent therapy, including clinically significant hepatitis and treatment discontinuation.⁵ Checkpoint-TKI combinations add expected adverse effects of multikinase inhibition to immune-related risks, although early ACC reports have not identified major unexpected safety signals.³

The most reliable safety conclusion is that these regimens are administrable but can be difficult in a population that often already has endocrine, hepatic, metabolic, or performance-status burdens related to ACC and prior treatment.⁵³ The practical implication is that modest average efficacy narrows the acceptable toxicity margin, so treatment goals, comorbidity, and symptom burden should weigh heavily in decision-making.

Role in Current Management and Research

Taken together, current evidence places combination immunotherapy and TKI-based strategies in ACC as selective or investigational options rather than established standards of care.¹² They do not replace surgery for resectable disease, and they have not displaced mitotane-based or chemotherapy-based systemic treatment for most patients with advanced ACC.¹² Their most plausible present-day use is in biomarker-enriched cases, after standard options, or in clinical trials.

This management position follows directly from the evidence limitations. What is reasonably well supported is that a minority of patients may derive meaningful and sometimes durable benefit.⁵³ What is not well supported is any broad comparative advantage over standard workflows in unselected ACC.² Future progress is likely to depend more on refining biologic selection and defining mechanisms of immune resistance than on combining agents indiscriminately.¹⁴

Included Articles

• PMID 33889439: In a six-patient prospective subgroup with advanced ACC, combined nivolumab plus ipilimumab produced a 33% objective response rate and 66% disease control rate, with two durable ongoing partial responses seen in MSI-H tumors. Toxicity was substantial, with grade 3/4 immune-related hepatitis common and frequent treatment discontinuation.⁵

• PMID 35158739: This review summarizes checkpoint inhibitor therapy in ACC, noting limited overall benefit in early trials despite biologic rationale from PD-L1 expression and a minority of mismatch repair-deficient or microsatellite-unstable tumors. It highlights combination strategies and modulation of the hormonal and vascular microenvironment as potential ways to improve responses.¹

• PMID 38473262: A 2024 systematic review and meta-analysis found that immune checkpoint inhibitors in advanced ACC have modest activity, with pooled objective response and disease control rates of 14% and 43%, median progression-free survival of 2.8 months, median overall survival of 13.9 months, and no clear advantage for combination regimens over monotherapy.²

• PMID 40220261: A pan-cancer bioinformatic analysis identified high ITGB3 expression as a risk factor associated with lower survival in ACC and linked it to an immunosuppressive tumor microenvironment, including reduced CD8-positive, Th1, and NKT cells and increased Tregs, Th2 cells, CTLA4, and PDCD1.⁴

• PMID 40938918: A multicenter phase II basket trial evaluated cabozantinib plus atezolizumab in advanced, progressive ACC after prior chemotherapy and/or mitotane, showing an objective response rate of 8.3%, median duration of response of 13.1 months, median progression-free survival of 2.9 months, and median overall survival of 13.5 months. Patients with ACC and Cushing syndrome had no responses, and the regimen had no unexpected toxicity.³

References

Footnotes

1. Endocrine and Neuroendocrine Tumors Special Issue-Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?. Cancers (Basel). 2022. PMID: 35158739. Local full text: 35158739.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷

2. The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis.. Cancers (Basel). 2024. PMID: 38473262. Local full text: 38473262.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³

3. Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A Multicohort, Basket, Phase II Trial (CABATEN/GETNE-T1914).. Clin Cancer Res. 2025. PMID: 40938918. Local full text: 40938918.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰

4. Pan-cancer analysis of ITGB3 as a potential prognostic and immunological biomarker.. Discov Oncol. 2025. PMID: 40220261. Local full text: 40220261.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

5. Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538.. Oncoimmunology. 2021. PMID: 33889439. Local full text: 33889439.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹