Tackling Unmet Needs in Small Cell Lung Cancer

With the arrival of immunotherapy to the small cell lung cancer (SCLC) armamentarium, combination approaches with targeted therapies are now in the pipeline to stimulate further clinical activity, such as adding PARP or CHK1 inhibitors, said Charles M. Rudin, MD, PhD, in a presentation during the 2019 International Lung Cancer Congress.

“There are a lot of new targets that are ripe for the picking and are beginning to emerge from preclinical data—and they’re ripe for moving into the clinic,” said Rudin, the Sylvia Hassenfeld Chair in Lung Cancer Research, chief, Thoracic Oncology, co-director, Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center.

While lung adenocarcinoma is subtyped with numerous drivers, SCLC is “much less defined when thinking about subsets and drivers, but we think this is beginning to change,” said Rudin. “Not that there has been tremendous progress on the clinical side, but I think the research in the laboratories is beginning to define subsets of SCLC that may be biologically relevant and potentially therapeutically targetable.”

Preclinical and human data have previously led to a model of subtypes based on 4 key transcription regulators believed to be key in driving oncogenic pathways in SCLC: achaete-scute homologue 1 (ASCL1/ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1), and POU class 2 homeobox 3 (POU2F3).¹ Within ASCL1 is DLL3, BCL2, CREBBP, and LSD1; NEUROD1 includes ANTXR1, LSH1, AURKA, INSM1++, ASCL1+/—, and MYC+; POU2F3 is IGF-1R and AURKA; and YAP1 includes AURKA and MYC+++ and SOX9+.

Prospective research has begun to demonstrate activity for some of these targets, including a phase II trial with AURKA inhibition in patients with relapsed SCLC who have c-MYC positivity. The AURKA inhibitor alisertib combined with paclitaxel led to a median progression-free survival (PFS) of 4.64 months compared with 2.27 months with placebo/paclitaxel in c-MYC—positive patients (HR, 0.29; 95% CI, 0.12-0.72).²

However, in those with c-MYC negativity, the addition of the AURKA inhibitor to paclitaxel was associated with a median PFS of 3.32 months versus 5.16 months for placebo and paclitaxel (HR, 11.8; 95% CI, 1.52-91.2).

The Arrival of Immunotherapy

The addition of checkpoint inhibitors to both the frontline and recurrent SCLC settings have been modest, Rudin explained, yet have provided a foundation for further research.

“It is a significant advance, [and] it is a small advance,” he added. “Both of these [survival] curves are unfortunately trending down pretty steeply, so we really need to do better. I think this does give us something to build on.”

The first checkpoint inhibitor approval for SCLC was for nivolumab (Opdivo), which the FDA indicated for the treatment of patients with SCLC with disease progression following platinum-based chemotherapy and 1 other line of therapy. The approval is based on data from the phase I/II CheckMate-032 trial, which showed that the objective response rate (ORR) was 12% (95% CI, 6.5-19.5) for nivolumab after platinum-based chemotherapy and 1 other prior line of therapy.³

In an exome-sequencing analysis of CheckMate-032, researchers identified that patients with high tumor mutational burden (TMB) may have a greater improvement in overall survival (OS) when treated with nivolumab. Patients with high-, medium-, and low-TMB had a median OS of 5.4 months, 3.9 months, and 3.1 months, respectively; the 1-year OS rates were 35.2%, 26.0%, and 22.1%, respectively.⁴

In March 2019, the FDA approved the combination of atezolizumab (Tecentriq) with carboplatin and etoposide for the frontline treatment of patients with extensive-stage SCLC. In the phase III IMpower133 trial, results showed that the median OS with atezolizumab was 12.3 months (95% CI, 10.8-15.9) versus 10.3 months in the placebo arm (95% CI, 9.3-11.3), leading to a 30% reduction in the risk for death (HR, 0.70; 95% CI, 0.54-0.91; P = .007).⁵

Most recently, in June 2019, the agency granted an accelerated approval to single-agent pembrolizumab (Keytruda) for the treatment of patients with metastatic SCLC who have disease progression on or after platinum-based chemotherapy and ≥1 other prior line of therapy. The decision was based on pooled data from cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 trials, which demonstrated that the PD-1 inhibitor elicited a 19% overall response rate (95% CI, 11%-29%) in this patient population.⁶

One data set that is eagerly anticipated in the community, Rudin said, is the phase III CASPIAN trial (NCT03043872) of durvalumab (Imfinzi) combined with standard etoposide and platinum-based chemotherapy as a first-line treatment in patients with extensive-stage SCLC. An announcement of the trial stated that the immunotherapy/chemotherapy combination demonstrated a statistically significant and clinically meaningful improvement in OS compared with standard chemotherapy alone.⁷ Based on these data, the FDA granted the PD-L1 inhibitor orphan drug status in this space.

New Directions

Preclinical data have demonstrated that by targeting PARP and the checkpoint kinase (CHK1) pathways, there is a significant increase in PD-L1 protein and surface expression.⁸

Moreover, DNA damage response inhibition also activates the STING/TBK1/IRF3 innate immune pathways, which lead to higher levels of CXCL10 and CCL5 chemokines that induce activation and function of cytotoxic T lymphocytes, overall providing a rationale to combine PARP or CHK1 inhibitors with immunotherapy in SCLC. In his presentation, Rudin highlighted 2 preclinical data sets with the CHK1 inhibitor prexasertib and with the PARP inhibitor olaparib (Lynparza), both in combination with an anti—PD-L1 antibody.

“These are pretty dramatic interactions between prexasertib or the PARP inhibitor olaparib. This seems to be activation through the cGAS/STING mechanism if you get a DNA damage … [then] you subsequently activate the immune system. The initial data has not been nearly as dramatic as this, but it does suggest a way forward if we can optimize the combinatorial properties of chemotherapy and targeted therapies … with immunotherapy.”

The current state of SCLC research is also evolving to focus on defining mechanisms of chemoresistance, specifically with the role of SLFN11, as well as epigenetic targeting with EZH2, and evaluating epigenetic vulnerabilities with LSD1 and BRD4.

DLL3, which is highly expressed on SCLC cells, could also be addressed with antibody-drug conjugates, bispecific T-cell engagers, CAR T-cell therapies, and radioconjugates.

Collaborative efforts have been underway to sift through the complexity of SCLC. The National Cancer Institute’s SCLC Consortium at Memorial Sloan Kettering Cancer Center, for example, is an exchange platform that supports data integration, data analysis, and SCLC researchers meet monthly to discuss research updates.

“This is entirely preclinical, but I think it has been a really powerful mechanism for us to learn a lot more about the biology of this disease,” said Rudin.

References

1. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19(5):289-297. doi: 10.1038/s41568-019-0133-9.

2. Owonikoko TK, Nackaerts K, Csoszi T, et al. Randomized phase 2 study of investigational aurora A kinase (AAK) inhibitor alisertib (MLN8237) + paclitaxel (P) vs placebo + P as second line therapy for small-cell lung cancer (SCLC). Ann Oncol. 2016;27(6):1423O. doi.org/10.1093/annonc/mdw389.01.

3. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstr 100).

4. Hellman MD, Callahan MK, Award MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell.2018;33(5):853-861. doi: 10.1016/j.ccell.2018.04.001.

5. Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220-2229. doi: 10.1056/NEJMoa1809064.

6. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) as Monotherapy for Patients with Metastatic Small Cell Lung Cancer (SCLC) with Disease Progression on or After Platinum-Based Chemotherapy and at Least One Other Prior Line of Therapy. Merck. Published June 18, 2019. https://bit.ly/2Kn2Tur. Accessed June 18, 2019.

7. Imfinzi Improves Overall Survival at Interim Analysis in the Phase III CASPIAN Trial in 1st-Line Extensive-Stage Small Cell Lung Cancer. AstraZeneca. Published June 27, 2019. https://bit.ly/2RFpKlz. Accessed June 27, 2019.

8. Sen T, Rodriguez BL, Chen L. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov. 2019;9(5):646-661.