Journal of Clinical Oncology July 13, 2026

Avatrombopag Versus Placebo for Persistent Chemotherapy-Induced Thrombocytopenia in GI Cancers: The Phase II ACT-GI Trial

Hanny Al-Samkari et al.

Bottom Line

In a phase II, double-blind, randomized trial of patients with gastrointestinal cancers and persistent chemotherapy-induced thrombocytopenia, avatrombopag successfully corrected and prevented the recurrence of thrombocytopenia, leading to early trial termination for efficacy.

Key Findings

1. The trial was closed to enrollment early at a planned interim analysis after meeting prespecified stopping criteria for dramatic efficacy.

2. The primary endpoint (successful correction of CIT and prevention of recurrence) was achieved by 70% (16 of 23) of patients receiving avatrombopag compared to only 17% (4 of 24) of patients receiving placebo (Z = 3.67, P < 0.001).

3. At the end of the on-cycle treatment period, the median platelet count was 157 × 10^9/L (IQR: 136-202) in the avatrombopag group versus 72 × 10^9/L (IQR: 68-134) in the placebo group.

4. Adverse events (AEs) and serious AEs occurred in 78% and 17% of patients receiving avatrombopag, respectively, compared with 46% and 0% of those receiving placebo; however, no serious AEs were considered related to the study drug, and no treatment-related AEs led to death or discontinuation.

Study Design

Design

Phase II RCT

Double-Blind

Sample

Patients

Duration

1 cycle

Median

Setting

Multicenter, US

Population Patients with gastrointestinal cancers and persistent chemotherapy-induced thrombocytopenia (platelet count ≤85 × 10^9/L on day 1 of a scheduled chemotherapy cycle despite adequate recovery time).

Intervention Avatrombopag (40 mg daily oral dosing)

Comparator Placebo

Outcome Successful correction of CIT and prevention of recurrence (defined as recovery of platelets to ≥100 × 10^9/L, no chemotherapy dose modification or delay, and prevention of CIT recurrence [platelets ≥100 × 10^9/L] at the end of the on-study cycle).

Study Limitations

• Small sample size (N=47) resulting from the early termination of the trial due to prespecified stopping criteria for efficacy.

• The trial was restricted to patients with gastrointestinal (GI) cancers, which may limit the direct generalizability of the findings to patients with other solid tumors or hematologic malignancies.

• An imbalance in total adverse events and serious adverse events was noted (higher in the avatrombopag arm), though none were deemed study drug-related by the investigators.

• Long-term durability and safety data were pending at the time of the primary publication, awaiting the completion of the ongoing open-label extension phase.

Clinical Significance

Avatrombopag represents a major, patient-centric breakthrough in the management of persistent chemotherapy-induced thrombocytopenia (CIT). By allowing for full-dose and on-time chemotherapy delivery without the need for weekly, hours-long clinic visits and injections required by off-label options like romiplostim, this oral TPO-RA provides an efficacious and convenient tool to maintain dose intensity in patients with GI malignancies.

Historical Context

Chemotherapy-induced thrombocytopenia (CIT) is a prevalent and challenging complication that forces potentially deleterious chemotherapy dose reductions and delays. For decades, there have been no widely approved therapies for CIT outside of China (where recombinant human thrombopoietin is used). Recombinant interleukin-11 (oprelvekin) was historically available but largely abandoned due to substantial toxicities. More recently, subcutaneous romiplostim (a weekly injectable peptibody TPO-RA) showed promise and achieved guideline inclusion for off-label use in persistent CIT, but its heavy logistical burden medicalized patients' lives. Avatrombopag, a second-generation, once-daily oral TPO-RA lacking dietary restrictions and the hepatotoxicity of eltrombopag, was tested in the ACT-GI trial to provide a much-needed, convenient oral alternative.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of avatrombopag differ from traditional treatments like platelet transfusions in the management of chemotherapy-induced thrombocytopenia?

Key Response

Avatrombopag is an oral thrombopoietin receptor agonist (TPO-RA) that stimulates megakaryopoiesis in the bone marrow to increase endogenous platelet production, addressing the root cause of suppression in CIT. In contrast, transfusions only provide temporary, exogenous replacement and carry risks of alloimmunization and transfusion reactions.

Resident

When evaluating a patient with GI cancer who develops isolated thrombocytopenia after FOLFOX therapy, what other etiologies must be ruled out before diagnosing persistent chemotherapy-induced thrombocytopenia and initiating a TPO-RA?

Key Response

Residents must consider oxaliplatin-induced immune-mediated thrombocytopenia, disseminated intravascular coagulation (DIC), hypersplenism (e.g., from oxaliplatin-induced portal hypertension or liver metastases), and bone marrow infiltration, as TPO-RAs are specifically indicated for megakaryocytic suppression, not consumptive or immune destructive processes.

Fellow

Given that GI cancers and their treatments inherently increase thrombotic risk, how should we balance the thromboembolic risks of TPO-RAs like avatrombopag with the need to maintain chemotherapy dose intensity?

Key Response

Fellows must navigate a nuanced risk-benefit ratio. TPO-RAs carry a risk of thromboembolic events, which is particularly concerning in mucin-producing GI adenocarcinomas with high baseline VTE risk. Careful monitoring of target platelet counts and minimizing overcorrection are critical when aiming to prevent chemotherapy dose delays.

Attending

The ACT-GI trial was stopped early for efficacy based on platelet recovery, but how should we evaluate whether the prevention of CIT translates into meaningful long-term clinical outcomes like progression-free or overall survival for our GI cancer patients?

Key Response

Attendings must contextualize surrogate endpoints. While correcting thrombocytopenia avoids chemotherapy dose reductions or delays, the ultimate question is whether maintaining relative dose intensity through TPO-RA use translates to improved oncologic survival, thereby offsetting the financial toxicity and potential thrombotic risks.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial was terminated early for efficacy. What are the statistical and methodological risks of early termination in a Phase II trial, particularly regarding the estimation of adverse event rates like thrombosis?

Key Response

Early stopping for efficacy often truncates the follow-up needed to accurately capture delayed or rare adverse events (e.g., VTEs) and can lead to an exaggerated treatment effect size (the winner's curse). Researchers must critically evaluate if the stopping boundaries adequately penalized the alpha for interim analyses.

Journal Editor

How does the choice of 'correction of thrombocytopenia' as the primary endpoint, rather than a clinical endpoint like 'reduction in clinically significant bleeding events' or 'maintenance of chemotherapy dose intensity', affect the trial's clinical validity?

Key Response

Editors must scrutinize endpoint selection. A laboratory endpoint (platelet count) is a surrogate that guarantees a high effect size for a TPO-RA but may not capture the true clinical benefit or harm. A rigorous reviewer would flag the lack of power to detect differences in bleeding or survival outcomes.

Guideline Committee

Current ASCO guidelines suggest considering TPO-RAs only for specific patients with CIT to avoid dose reductions when other options fail. Does the early efficacy demonstrated in the Phase II ACT-GI trial warrant upgrading avatrombopag to a first-line recommendation for CIT in solid tumors?

Key Response

Guideline committees must weigh Phase II data against existing standards. While ACT-GI shows strong efficacy for avatrombopag, upgrading the recommendation level would likely require Phase III data demonstrating that the intervention safely improves chemotherapy delivery and survival without unacceptable VTE risks, currently keeping it as a conditional recommendation.

Clinical Landscape

Noteworthy Related Trials

2018

ADAPT-1 and ADAPT-2

n = 435 · Gastroenterology

Tested

Avatrombopag 40mg or 60mg

Population

Patients with chronic liver disease and severe thrombocytopenia

Comparator

Placebo

Endpoint

Avoidance of platelet transfusion or rescue procedure

Key result: Avatrombopag significantly increased the proportion of patients who did not require platelet transfusions or rescue procedures compared to placebo.

2019

Romiplostim for Chemotherapy-Induced Thrombocytopenia Trial

n = 60 · JCO

Tested

Romiplostim weekly injection

Population

Patients with solid tumors and persistent chemotherapy-induced thrombocytopenia

Comparator

Standard of care

Endpoint

Platelet recovery to 100x10^9/L and resumption of chemotherapy

Key result: Romiplostim successfully corrected thrombocytopenia in the vast majority of patients, allowing them to resume and maintain their chemotherapy schedules without dose reductions.

2019

Eltrombopag for Chemotherapy-Induced Thrombocytopenia Phase II Trial

n = 75 · Lancet Haematol

Tested

Eltrombopag 100mg daily

Population

Patients with advanced solid tumors receiving gemcitabine-based chemotherapy

Comparator

Placebo

Endpoint

Proportion of patients requiring chemotherapy dose delays or reductions

Key result: Eltrombopag did not significantly reduce chemotherapy dose delays or reductions compared to placebo despite being well tolerated.

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