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2021 WCLC Highlights

CME

Independent Conference Coverage of the IASLC 2021 World Conference on Lung Cancer

Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™

Released: November 18, 2021

Expiration: November 17, 2022

Anne Chiang
Anne Chiang, MD, PhD
Thomas Stinchcombe
Thomas Stinchcombe, MD
CME/CE Information

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TROPION-PanTumor01–Updated NSCLC Cohort: Study Design

Thomas E. Stinchcombe, MD:
Datopotamab deruxtecan is an antibody–drug conjugate that targets TROP2, a transmembrane glycoprotein that is overexpressed in some lung cancers and is associated with poor prognosis.43 This antibody–drug conjugate comprises a fully humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker.44

TROPION-PanTumor01 is a phase I dose-escalation/dose-expansion trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in a variety of tumors, including advanced NSCLC. At WCLC 2021, Garon and colleagues45 presented updated results from the advanced NSCLC cohort of TROPION-PanTumor01, with a data cutoff of April 6, 2021. The patients in this cohort had pretreated, relapsed/refractory advanced or metastatic NSCLC. They must have had a pretreatment biopsy, but patients were not selected based on TROP2 expression. In the dose-escalation phase, 8 mg/kg every 3 weeks was established as the maximum tolerated dose, and the dose expansion included cohorts that received datopotamab deruxtecan at 4 mg/kg, 6 mg/kg, or 8 mg/kg every 3 weeks. The primary trial objectives were maximum tolerated dose, safety, and tolerability, and secondary objectives included efficacy, pharmacokinetics, and assessment of antidrug antibodies.

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TROPION-PanTumor01–Updated NSCLC Cohort: Baseline Characteristics

Thomas E. Stinchcombe, MD:
Looking at the demographics of this cohort, the median age was approximately 60 years in each dose subgroup. The number of patients who had 3 or more lines of prior therapy was approximately 50% to 60%. Nearly all the patients had received platinum‑based chemotherapy and 74% to 88% had received immunotherapy, so this was a heavily pretreated patient population.

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TROPION-PanTumor01–Updated NSCLC Cohort: Safety

Thomas E. Stinchcombe, MD:
Safety was one of the primary endpoints. The rate of grade ≥3 AEs increased with dose, from 30% in the 4-mg/kg group to 54% in the 6-mg/kg group and 58% in the 8 mg/kg group. Dose discontinuations, interruptions, and reductions also showed a trend toward higher incidence in patients who received the 8-mg/kg dose. Focusing on the specific toxicity of drug-related interstitial lung disease, rates were highest with the 8-mg/kg dose, including 3 cases of grade 5 interstitial lung disease, and this dose has been discontinued for further development.

The most common treatment-emergent toxicities are shown in the figure on the right, with color-coding according to dose and grade ≥3 events indicated by striped boxes. The most common treatment-emergent AEs were nausea, stomatitis, and alopecia, all of which are standard chemotherapy toxicities, and most of these events were grade 1/2.

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TROPION-PanTumor01–Updated NSCLC Cohort: Antitumor Activity

Thomas E. Stinchcombe, MD:
Datopotamab deruxtecan had a fairly consistent response rate around 25% in each of the 3 dose cohorts. The responses were generally durable, with a median DoR that was not evaluable in the 4-mg/kg cohort, 10.5 months in the 6-mg/kg group, and 9.4 months in the 8-mg/kg group. These are relatively large cohorts, so I expect these may be fairly accurate estimates of the response rate.

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TROPION-PanTumor01–Updated NSCLC Cohort: Clinical Implications

Thomas E. Stinchcombe, MD:
In the NSCLC cohort of TROPION-PanTumor01, datopotamab deruxtecan demonstrated preliminary activity across all expansion doses and had a tolerable toxicity profile. The dose-escalation and dose-expansion cohorts identified 6 mg/kg as the dose for further investigation. We’re now awaiting various ongoing trials that will help us define the antitumor activity and potential role of this agent as second‑line treatment for advanced NSCLC.

Anne Chiang, MD, PhD:
I agree that the preliminary safety and efficacy data for datopotamab deruxtecan in this heavily pretreated cohort of patients with advanced NSCLC looks promising and we should keep our eye on it as a future option for patients who cannot receive immunotherapy.

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Which of the following results was reported by Garon and colleagues at WCLC 2021 from the NSCLC patient cohort of the phase I dose-escalation/dose-expansion TROPION-PanTumor01 study evaluating datopotamab deruxtecan, an investigational antibody–drug conjugate targeting TROP2?
Phase I Trial of Mesothelin-Targeted CAR T-Cell Therapy: Study Design

Anne Chiang, MD, PhD:
Although multiple CAR T-cell therapies are approved for use in patients with hematologic malignancies, the application of this treatment strategy to solid tumors has been challenging. At WCLC 2021, Adusumilli and colleagues46,47 presented results of a phase I study of mesothelin‑targeted CAR T‑cells administered intrapleurally (with or without subsequent treatment with pembrolizumab) in 27 patients with malignant pleural cancers, including malignant pleural mesothelioma (n = 25), metastatic lung cancer (n = 1), or metastatic breast cancer (n = 1), with the primary endpoint of safety.

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Phase I Trial of Mesothelin-Targeted CAR T-Cell Therapy: Baseline Characteristics in Patients With MPM

Anne Chiang, MD, PhD:
Looking at patient baseline characteristics, the key point is that this was a group of highly selected patients with good PS who were most likely to tolerate the therapy and did not necessarily have the burden of disease to require an immediate response.

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Phase I Trial of Mesothelin-Targeted CAR T-Cell Therapy: Safety (Primary Endpoint)

Anne Chiang, MD, PhD:
In this highly selected population, the CAR T-cell therapy was well tolerated; no dose-limiting toxicities were observed and the maximum tolerated dose was not reached. No patients died and all grade 4 AEs were laboratory abnormalities that resolved. There was no grade >2 cytokine-release syndrome or neurotoxicity. Within 2 weeks, 41% of patients were readmitted for monitoring with fever, fatigue, or malaise.

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Phase I Trial of Mesothelin-Targeted CAR T-Cell Therapy: Preliminary Efficacy Data

Anne Chiang, MD, PhD:
Preliminary efficacy data was shown for 23 patients with malignant pleural mesothelioma. Treatment with mesothelin CAR T-cell therapy with or without pembrolizumab achieved a median OS of 17.7 months, with a 1-year OS rate of 74%, and a median time-to-next treatment of 15.3 months, with a 1-year time-to-next treatment rate of 53%.

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Phase I Trial of Mesothelin-Targeted CAR T-Cell Therapy: Clinical Implications

Anne Chiang, MD, PhD:
This study showed the feasibility of locally delivered CAR T-cell therapy for select patients with malignant pleural cancers. Functional T‑cell studies and correlative studies showed that intrapleural administration of CAR T-cell therapy can actually have a systemic effect on the immune system. Although this is a space to watch for, it is early days, and these data will not affect our SoC for a while.

Thomas E. Stinchcombe, MD:
The development of CAR T‑cell therapy has shown a lot of promise in hematologic malignancies, and we would like to transition this success to the treatment of solid tumors in general and thoracic oncology in particular. I agree that the preliminary evidence from this phase I trial reported at WCLC 2021 demonstrate the safety and efficacy of this approach in patients with malignant pleural cancers, and I’m intrigued to see if this will continue in larger cohorts. Questions about the logistics remain, but CAR T-cells are a promising new mechanism that deserves further attention.

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