Department of Hematology and Medical Oncology
Co-Leader, Thoracic Oncology
Taofeek K. Owonikoko, MD, PhD, has disclosed that he has received funds for research support paid to his institution from AbbVie, Aeglea BioTherapeutics, Amgen, Astellas, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Celgene, Corvus Pharmaceuticals, Fujifilm, G1 Therapeutics, Incyte, Loxo Oncology/Lilly, Merck, Novartis, Pfizer, Regeneron, Stemcentrx, and United Therapeutics; has received consulting fees from AbbVie, Amgen, ARMO BioSciences, AstraZeneca, Bayer, BerGenBio, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisai, EMD Serono, G1 Therapeutics, Heron Therapeutics, Lilly, MedImmune, Novartis, PharmaMar, Sandoz, Seattle Genetics, Takeda, and Xcovery; has received fees for non-CME/CE services from EMD Serono and Roche/Genentech; and has ownership interest in Cambium Oncology.
Coming off the tails of results from the phase III IMpower133 trial that were reported at the International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer and the subsequent approval of atezolizumab plus carboplatin/etoposide for first-line treatment of small-cell lung cancer (SCLC), it was relatively quiet for SCLC at ASCO this year. However, reports from a couple of phase II studies that looked at treatment in the second-line setting could have implications in the near future for how we treat our patients with SCLC in the frontline setting.
CDK4/6 Inhibition as Myelopreservation in Patients With SCLC Receiving Chemotherapy
Trilaciclib is a highly selective and reversible investigational CDK4/6 inhibitor that was designed to protect the bone marrow, including preservation of hematopoietic stem and progenitor cells and immune system function, while patients are receiving cytotoxic chemotherapy. This is an important distinction from other CDK4/6 inhibitors (ie, palbociclib, abemaciclib, and ribociclib) that were developed to target tumor cells and that are approved for patients with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.
The myeloprotectant activity of trilaciclib requires an intact retinoblastoma (RB) gene: When cells with an intact RB gene are treated with CDK4/6 inhibitors, they enter cell cycle arrest (ie, cell cycle progression is blocked) and are thus less susceptible to damage from chemotherapy. The vast majority of SCLC tumors have lost a functional RB gene and RB protein, often due to complex genomic translocations, so trilaciclib can be used in patients with SCLC receiving chemotherapy to transiently protect normal bone marrow tissue (with functional RB activity) while leaving SCLC cells (without functional RB activity) susceptible to chemotherapy’s cytotoxic effects.
At ASCO 2019, a proof-of-concept trial for trilaciclib as a myeloprotectant in second-line treatment for SCLC was reported. In this randomized phase II study, which I was involved in as coinvestigator, patients with previously treated extensive-stage SCLC were treated with second-line topotecan plus trilaciclib 240 mg/m2 or placebo. For the 60 patients who received topotecan at a dose of 1.5 mg/m2, addition of trilaciclib (n = 32) led to an increase in the mean number of chemotherapy cycles completed (5 cycles [standard deviation: 4.1] vs 4 [standard deviation: 3.4] with placebo [n = 28]); a decrease in the need for topotecan dose reductions (19% vs 32% with placebo); an almost 50% lower event rate (per 100 cycles) of all-cause dose reductions (5.1 vs 11.6 with placebo); and substantially improved rates of myelosuppression, including decreases in severe neutropenia (40.6% vs 75.9% with placebo; P = .016), febrile neutropenia (6.3% vs 17.2% with placebo), and grade 3/4 anemia (38.7% vs 63% with placebo). A similar phase Ib/II study combining trilaciclib with first-line carboplatin plus etoposide for extensive-stage SCLC also showed that addition of a CDK4/6 inhibitor to cytotoxic chemotherapy mitigated myelosuppression, and of importance, preserved immune system function as well.
Going forward, I think the value of this strategy will be to improve outcomes in the frontline setting for patients with advanced SCLC, where combination immunotherapy plus chemotherapy has become standard of care, by preserving immune system function and minimizing hematologic toxicities. However, before this strategy is adopted into clinical practice, additional randomized trials will be required to further assess the potential benefit of this approach for our patients with extensive-stage SCLC. In fact, a randomized phase II study evaluating the safety and efficacy of adding trilaciclib to first-line atezolizumab plus carboplatin and etoposide is ongoing (NCT03041311).
Lurbinectedin: A Novel Anticancer Drug With Promising Efficacy in SCLC
Lurbinectedin, a synthetic analog of the marine alkaloid trabectedin, is a novel anticancer drug that, in part, functions by selectively inhibiting active transcription of protein-coding genes through binding to promoters and irreversibly stalling elongating RNA polymerase II on the DNA template, thereby leading to double-stranded DNA breaks and apoptosis. SCLC has many aberrations in promoters of protein-coding genes, and lurbinectedin seems to have particular activity against gene-promoting alterations in cancer cells, so it was anticipated that this agent would be especially effective in SCLC.
At ASCO 2019, mature results from the SCLC cohort (n = 105) of a phase II basket trial of single-agent lurbinectedin 3.2 mg/m2 every 3 weeks were reported. Patients with relapsed SCLC, including those with both platinum‑sensitive and platinum‑resistant disease, achieved an ORR of 35.2% (all confirmed PRs), a disease-control rate of 68.6%, and a median duration of response of 5.3 months. Even more impressive were the results achieved in patients with platinum-sensitive relapsed SCLC (n = 60), including an ORR of 45.0% (vs 22.2% in resistant disease), a disease control rate of 81.7% (vs 51.1% in resistant disease), a median duration of response of 6.2 months (vs 4.7 months in resistant disease), and a median PFS of 4.6 months (vs 2.6 months in resistant disease), which is significantly longer than typically expected for this population of patients.
Lurbinectedin has also been evaluated in combination with doxorubicin for advanced SCLC, with initial results from a phase Ib/II study showing compelling second-line activity: 37% ORR overall and 53% ORR in patients with platinum-sensitive disease. We currently await the report of the ongoing, fully accrued phase III ATLANTIS trial (N = 613) evaluating lurbinectedin plus doxorubicin vs standard-of-care treatment (topotecan or cyclophosphamide/doxorubicin/vincristine) in patients with SCLC for whom 1 prior platinum-based chemotherapy regimen failed.
I anticipate lurbinectedin may become available in the clinic for patients with SCLC in the near future. However, which regimen gains regulatory approval, whether single-agent or in combination with chemotherapy, is not yet clear. As I mentioned, the definitive randomized phase III ATLANTIS trial is testing lurbinectedin in combination with doxorubicin. However, the phase II results of single-agent lurbinectedin from ASCO described above are comparable to the early phase data that led to the phase III trial evaluating the combination. It does appear that lurbinectedin is better tolerated as a single agent. When it was combined with doxorubicin, many patients required the use of growth factor support in order to tolerate associated hematologic toxicities. With single-agent use, the rate of cytopenias was considerably lower, and the need for growth factor support was less frequent. I suspect that if lurbinectedin is approved as a combination regimen, many patients who start with the combination may eventually end up switching to single-agent lurbinectedin due to toxicities if they have to stay on the regimen for the long term.
Ongoing Trials in SCLC: New Ways to Target DLL3
At ASCO 2019, we also heard about ongoing trials in SCLC centered on new ways to target delta‑like ligand 3 (DLL3), which is aberrantly expressed on the cell surface in more than 80% of SCLC tumors but rarely in normal adult tissues (ie, it is only found in the cytoplasm of neurons and pancreatic islet and pituitary cells). Initial attempts to target DLL3 in SCLC with the antibody-drug conjugate rovalpituzumab tesirine (Rova-T) showed promising phase I efficacy, but its subsequent development has been slowed by disappointing phase II/III results and off-target toxicities.
Two new approaches of targeting DLL3 in SCLC include a bispecific T-cell engager (BiTE) antibody construct and patient-specific chimeric antigen receptor T-cell (CAR-T) therapy. Half-life extended BiTE antibody construct AMG 757 targets DLL3 on SCLC cells and CD3 on T-cells as a strategy to transiently recruit immune cells into the tumor microenvironment, thereby leading to direct tumor lysis by activated T-cells. A phase I clinical trial of AMG 757 in patients with relapsed/refractory SCLC whose disease has progressed after at least 1 platinum-based chemotherapy is ongoing, with enrollment open at many sites in the United States, Australia, Japan, and Europe (NCT03319940). A little bit further behind in clinical development than AMG 757 is the DLL3-directed CAR-T therapy AMG 119, which is an adoptive cellular therapy that involves genetically modifying a patient’s autologous cytotoxic T-cells to express a transmembrane CAR construct that targets them specifically to DLL3-positive SCLC tumor cells. A phase I clinical trial of AMG 119 in patients with relapsed/refractory SCLC whose disease has progressed after at least 1 platinum-based chemotherapy is currently enrolling at select sites in the United States (NCT03392064). I would encourage our colleagues in the academic and community settings to consider these studies for their patients.
For more information on optimal management of SCLC in 2019, please visit https://www.clinicaloptions.com/oncology/programs/current-sclc-care.
Do you consider referring your patients with SCLC and disease progression on standard-of-care therapies to clinical trials? Please share your experiences in the comments box below.