A phase II clinical trial conducted in Japan has shown that adding the immunotherapy drug atezolizumab to standard chemotherapy significantly improves outcomes for patients with advanced thymic carcinoma, a rare and aggressive cancer with limited treatment options.
The MARBLE trial, results of which were published in The Lancet Oncology, evaluated the combination of atezolizumab with carboplatin and paclitaxel in 48 patients with recurrent or metastatic thymic carcinoma who had not received prior systemic therapy.
Impressive Response Rates Exceed Expectations
The combination therapy demonstrated an objective response rate of 56% (27 of 48 patients), all of which were partial responses. This substantially exceeded the pre-established clinically meaningful threshold of 30% (P < .0001), which was based on historical response rates to platinum-based chemotherapy in this patient population.
An additional 20 patients (42%) achieved stable disease, resulting in a remarkable disease control rate of 98%. Patients experienced a median target lesion reduction of 35.8%.
"Platinum-based chemotherapy has been recommended by the NCCN guidelines for chemotherapy-naive advanced or recurrent thymic carcinoma for more than 10 years, but its effectiveness was unsatisfactory," noted lead study author Dr. Takehito Shukuya from Juntendo University Graduate School of Medicine in Tokyo.
Survival Benefits and Duration of Response
The median follow-up period was 15.3 months. The trial reported a median progression-free survival of 9.6 months (95% CI, 7.7-14.8 months), while median overall survival had not been reached at the time of analysis (95% CI, 19.2 months to not estimable).
The median duration of response was 6.4 months according to independent central review and 10.2 months based on investigator assessment. These results suggest potential for durable benefit in a subset of patients.
Treatment Protocol and Patient Characteristics
In the trial, patients received atezolizumab (1,200 mg), carboplatin (AUC = 6), and paclitaxel (200 mg/m²) every three weeks for up to six cycles. This was followed by maintenance atezolizumab (1,200 mg every three weeks) for up to two years or until disease progression or unacceptable toxicity.
The study population had a median age of 67.5 years, with 60% being male. Most patients (71%) had squamous cell carcinoma histology, and 52% presented with Masaoka stage IVB disease. Nearly all participants (94%) had not received prior chemotherapy.
Safety Profile and Adverse Events
All patients experienced some adverse effects, with the most common being peripheral sensory neuropathy (88%), alopecia (83%), and neutropenia (77%). Grade 3 or higher toxicities occurred in 75% of patients, primarily neutropenia (56%), leukopenia (33%), and febrile neutropenia (23%).
Immune-related adverse events were also observed, with severe skin disorders (17%) and liver dysfunction or hepatitis (8%) being the most frequent serious immune-mediated toxicities. Six patients discontinued treatment due to adverse events, and 63% required chemotherapy dose reductions. Importantly, no treatment-related deaths occurred.
Implications for Clinical Practice
The investigators concluded that "the addition of atezolizumab to carboplatin and paclitaxel conferred clinically meaningful antitumor activity with a manageable safety profile" and suggested that this combination "might become a viable treatment option for previously untreated advanced or recurrent thymic carcinoma."
This finding is particularly significant given the limited therapeutic options for thymic carcinoma, a rare malignancy arising from the thymus gland. Standard platinum-based chemotherapy has shown modest efficacy, while immune checkpoint inhibitor monotherapy has demonstrated moderate activity in previously treated patients.
The MARBLE trial results suggest that combining immunotherapy with chemotherapy may provide superior outcomes compared to either approach alone, potentially establishing a new standard of care for this challenging malignancy.
Further studies with larger patient populations and longer follow-up will be needed to confirm these promising findings and determine whether the combination therapy leads to improved long-term survival for patients with this rare and difficult-to-treat cancer.
