CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: September 01, 2022
Expiration: August 31, 2023
Stephen V. Liu, MD:
First-line atezolizumab or durvalumab combined with platinum/etoposide is the current standard-of-care therapy for ES-SCLC, based on results from the IMpower133 study of atezolizumab and the CASPIAN trial of durvalumab,61-63 but there is still room for improvement in outcomes for these patients.
Toward this end, we saw results at ASCO 2022 from the large phase III SKYSCRAPER‑02 trial, on which I was a coauthor, that assessed the addition of tiragolumab, an anti‑TIGIT antibody, to chemotherapy/IO. Interest in tiragolumab was sparked after the phase II CITYSCAPE trial showed a significant improvement in PFS and OS in untreated patients with PD‑L1–high advanced NSCLC when combined with atezolizumab.64 The rationale for evaluating tiragolumab in frontline treatment for SCLC, is in part that the poliovirus receptor is overexpressed in SCLC, and poliovirus receptor is the ligand for TIGIT.65
SKYSCRAPER‑02 was a randomized, double-blind, placebo-controlled phase III study of frontline atezolizumab plus chemotherapy with or without tiragolumab in patients with ES-SCLC and no previous systemic treatment.66 Treated or untreated asymptomatic brain metastases were permitted.
Patients were randomized to receive tiragolumab in addition to atezolizumab with carboplatin/etoposide for induction and tiragolumab plus atezolizumab maintenance, or placebo plus atezolizumab with carboplatin/etoposide for induction and atezolizumab plus placebo for maintenance. Coprimary endpoints were OS and investigator-assessed PFS in the primary analysis set including all randomized patients without the presence or history of brain metastases at baseline. Secondary endpoints were PFS and OS in all randomized patients, ORR, DoR, safety, and pharmacokinetics.
Stephen V. Liu, MD:
Tiragolumab did not improve efficacy. There was no difference in either median PFS or OS by treatment arm in the primary analysis set including patients without brain metastases, or in the full analysis including all patients.66 Although this is an interim survival endpoint, this study will not show an impact with longer follow-up.
In the primary analysis set, the median PFS was 5.4 months in the tiragolumab arm vs 5.6 months with placebo (stratified HR: 1.11; 95% CI: 0.89-1.38; P = .3504). The median OS was 13.6 months on both arms (stratified HR: 1.04; 95% CI: 0.79-1.36; P = .7963).
Stephen V. Liu, MD:
In the full analysis set, survival outcomes were broadly similar.66 The median PFS was 5.1 months with tiragolumab vs 5.4 months with placebo (stratified HR: 1.08; 95% CI: 0.89-1.31). The median OS was 13.1 months vs 12.9 months, respectively (stratified HR: 1.02; 95% CI: 0.80-1.30).
The ORR in the tiragolumab-containing arm was 71%, with a DoR of 4.3 months as compared to an ORR of 66% in the placebo arm, with a DoR of 5.1 months.
Stephen V. Liu, MD:
This study allowed patients with untreated brain metastases, who were not included in the IMpower133 trial of atezolizumab with chemotherapy in ES-SCLC.62 In a subgroup analysis of SKYSCRAPER-02, median OS in patients with untreated brain metastases was 10.2 months in the placebo arm, which seems to compare relatively well with the 12.3 months of median OS reported in IMpower133 in patients receiving atezolizumab plus chemotherapy.62,66 So, this study does validate that approach in patients with untreated brain metastases.
Stephen V. Liu, MD:
There was no significant increase in overall toxicity with addition of tiragolumab to atezolizumab plus chemotherapy, with an any-grade AE rate of 99.6% and a rate of grade 3/4 AEs of 64% in both arms.66 The most common all-cause AEs were anemia, neutropenia, alopecia, and constipation.
There were more immune‑mediated AEs in the tiragolumab arm than the placebo arm (53.6% vs 48.0%, respectively). Common immune-mediated AEs included rash, hepatitis, hypothyroidism, hyperthyroidism, and infusion-related reactions.
Stephen V. Liu, MD:
SKYSCRAPER-02 provides definitive evidence that adding tiragolumab to atezolizumab plus carboplatin/etoposide in the frontline setting does not improve outcomes in an unselected population of patients with ES-SCLC. For me, this was a fairly disappointing study, although I do not think we can necessarily extrapolate the results to other disease settings.
What the study did do, however, was validate the current standard approach of using carboplatin, etoposide, and atezolizumab in untreated patients with ES-SCLC, as the OS in both treatment arms compared favorably to the IMpower133 trial.
Zofia Piotrowska, MD, MHS:
I agree. I think this is not a strategy that we can use in SCLC. There are other TIGIT studies ongoing and I am hopeful that this will be a more effective therapy in other tumor types.
Stephen V. Liu, MD:
Lurbinectedin is a selective inhibitor of oncogenic transcription that is approved by the FDA as monotherapy for the treatment of adults with metastatic SCLC and disease progression on or after platinum-based chemotherapy.67 Approval was based on the findings of an open-label, single-arm phase II trial of lurbinectedin 3.2 mg/m2 administered as a 60-minute infusion every 21 days in adults with ES-SCLC after failure of 1 previous platinum-based chemotherapy regimen.68 After a median follow-up of 17.1 months, the ORR was 35.2%.
The phase III ATLANTIS trial compared lurbinectedin 2.0 mg/m2 plus doxorubicin vs investigator’s choice of cyclophosphamide/doxorubicin/vincristine or topotecan in relapsed ES-SCLC after 1 previous line of platinum-containing chemotherapy.69
We have heard previously that the lurbinectedin combination did not improve OS compared with standard chemotherapy. However, an important feature of this study was that after patients received 10 cycles of the doxorubicin and lurbinectedin combination, they then switched to lurbinectedin monotherapy as maintenance. A post hoc analysis of ATLANTIS presented at ASCO 2022 focused on outcomes in the patients who received combination therapy with lurbinectedin 2 mg/m2 and then moved on to lurbinectedin monotherapy at the higher standard dose of 3.2 mg/m2.70 So although, in a sense, patients were de‑escalating by removing doxorubicin, in a different sense, they were escalating by increasing the dose of lurbinectedin.
Stephen V. Liu, MD:
Single-agent lurbinectedin as maintenance therapy was surprisingly effective. For many patients, the maximum percent reduction in tumor size occurred when they were receiving lurbinectedin monotherapy.70 Of the 19 patients who achieved SD with combination therapy, 2 patients subsequently achieved a PR and 1 patient achieved a CR on lurbinectedin maintenance. Among the 26 patients who had a PR with lurbinectedin plus doxorubicin, 3 went on to have a CR with lurbinectedin monotherapy, although 8 did eventually have disease progression.
Stephen V. Liu, MD:
Overall, the median OS in these patients was impressive at 20.7 months (95% CI: 15.7-24.8).70 In patients with a chemotherapy‑free interval of ≥180 days, the median OS was 21.2 months (95% CI: 16.8-33.6), whereas for those with a chemotherapy‑free interval <180 days, the median survival was 14.2 months (95% CI: 11.7-24.8), which is lower but still quite impressive.
Stephen V. Liu, MD:
There were no new safety signals.70 The primary grade ≥3 TRAE seen with lurbinectedin was myelosuppression. Grade ≥3 lymphopenia occurred in 36%, grade ≥3 anemia in 16%, and grade ≥3 neutropenia and thrombocytopenia in 12%. Febrile neutropenia was reported in 2 (4%) patients during lurbinectedin monotherapy.
Stephen V. Liu, MD:
Overall, I think these data reinforce the sense that ATLANTIS was not the right study design to demonstrate the efficacy of lurbinectedin in this patient population. The dose does seem to be important and at higher doses of lurbinectedin, responses are more likely.
Lurbinectedin is under evaluation in other phase III trials in patients with SCLC, including the LAGOON study comparing single-agent lurbinectedin or the combination of lurbinectedin plus irinotecan vs topotecan or irinotecan in relapsed SCLC (NCT05153239). The randomized phase III IMforte study is looking at lurbinectedin in combination with atezolizumab vs atezolizumab alone as maintenance therapy in patients with SCLC who received frontline induction with carboplatin, etoposide, and atezolizumab (NCT05091567). By moving lurbinectedin earlier in the disease process, we may further improve outcomes, because it is clear that this drug is active.
Zofia Piotrowska, MD, MHS:
I agree. I think lurbinectedin is an active drug but ATLANTIS did not assess the efficacy of lurbinectedin monotherapy at what seems to be the effective dose. This post hoc analysis shows that lurbinectedin is most active when given at that 3.2-mg/kg dose and that this is an active therapy for our patients. I currently use it in the later‑line setting, but I hope that the studies you mentioned may move it earlier in the disease course for patients with SCLC.
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