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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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ATLANTIS: Study Design

Anne Chiang, MD, PhD:
We’ll start with the phase III ATLANTIS trial, which evaluated the combination of lurbinectedin and doxorubicin in patients with previously treated SCLC. Lurbinectedin is approved by the FDA for use as a single agent, administered at 3.2 mg/m2 every 3 weeks in patients with metastatic SCLC and disease progression on or after platinum-based chemotherapy.1 This approval was based on a phase II trial in which lurbinectedin was associated with an overall response rate (ORR) of 35%.2

The randomized phase III ATLANTIS trial compared the efficacy and safety of lurbinectedin plus doxorubicin vs an investigator-chosen control regimen of topotecan or cyclophosphamide, doxorubicin, and vincristine (CAV) in 614 patients with extensive-stage SCLC who had received 1 prior line of chemotherapy (other lines of biologic therapy allowed) and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0‑2.3 Patients with refractory disease were excluded. The primary endpoint was overall survival (OS).

Because of overlapping toxicities between doxorubicin and lurbinectedin, mainly myelosuppression, the dosage of lurbinectedin chosen for the experimental arm of this trial was 2 mg/m2.

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ATLANTIS: Baseline Characteristics

Anne Chiang, MD, PhD:
Baseline characteristics were generally well matched between arms. There were a few never-smokers (6%) and 15% to 16% of patients had central nervous system (CNS) disease.

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ATLANTIS: OS in ITT Population

Anne Chiang, MD, PhD:
There was no significant difference in OS between the 2 arms, with a median OS of 8.6 months with lurbinectedin plus doxorubicin vs 7.6 months with topotecan or CAV. Subset analyses showed no differences between arms based on stratification factors.

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ATLANTIS: PFS by Independent Review

Anne Chiang, MD, PhD:
Median progression-free survival (PFS) outcomes were also not significantly different between arms.

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ATLANTIS: PFS by Stratification Factors

Anne Chiang, MD, PhD:
A subgroup analysis of PFS showed that patients with CNS metastases had less benefit with lurbinectedin plus doxorubicin than those without CNS metastases. This is notable as CNS metastases are prevalent among patients with SCLC.

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ATLANTIS: Response

Anne Chiang, MD, PhD:
ORR was also very similar between the 2 treatment arms, at approximately 30%. Patients with a longer chemotherapy‑free interval tended to experience more benefit with lurbinectedin plus doxorubicin: The ORR in the lurbinectedin/doxorubicin arm for patients with a chemotherapy‑free interval after first-line therapy of at least 180 days was 41% vs 33% and 20% for 90-179 days and 90 days or fewer, respectively. However, patients with a longer chemotherapy-free interval tend to do better in general.

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ATLANTIS: Safety

Anne Chiang, MD, PhD:
The combination of lurbinectedin plus doxorubicin was fairly well tolerated. There was significantly less grade ≥3 myelosuppression and lower rates of discontinuations due to AEs in the combination arm as compared with topotecan or CAV.

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ATLANTIS: Clinical Implications

Anne Chiang, MD, PhD:
As we consider the lack of benefit with lurbinectedin plus doxorubicin compared with chemotherapy in this trial, we should consider that the lurbinectedin dose used was lower than the FDA-approved single‑agent dosage (2.0 vs 3.2 mg/m2). This may be part of the reason we did not see improved outcomes with the combination of lurbinectedin and doxorubicin compared with chemotherapy. This trial did confirm that chemotherapy‑free interval is an important prognostic factor to second-line therapy in relapsed SCLC. The results also indicate that using OS as the primary endpoint in relapsed SCLC remains a difficult challenge. Future combinations of lurbinectedin with immune checkpoint inhibitors and other agents, such as irinotecan, may be an interesting approach to follow.

I also would like to point out that both pembrolizumab and nivolumab received FDA approval on the basis of smaller phase II studies and then had their approvals withdrawn based on findings from subsequent larger randomized, phase III trials.4-8 However, I don’t think the ATLANTIS study will affect the approval of lurbinectedin in this way because of the use of the lower dose in this study. I don’t think the trial speaks to the same question.

Thomas E. Stinchcombe, MD:
Yes, many people have adopted the use of lurbinectedin following its accelerated FDA approval based on the phase II results. The lack of an OS benefit with lurbinectedin plus doxorubicin in this phase III trial is somewhat sobering. I agree that ongoing trials with lurbinectedin may help define its role in metastatic SCLC. Patients with SCLC who have progressed on platinum chemotherapy with immunotherapy have very limited treatment options, so I’m hopeful that lurbinectedin will continue to be available for these patients while other trials are ongoing.

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