Poor Survival Rates Spur Research in Immunotherapy Combinations, PARP Inhibitors in SCLC

Current Treatment

Despite advances in small cell lung cancer (SCLC), overall 5-year survival remains at 5% to 10%. At the time of presentation, approximately 30% of patients with SCLC have limited stage (LS) disease, which is confined to the mediastinum, the hemithorax, or the supraclavicular lymph nodes. The remaining patients, who have extensive-stage (ES) SCLC, have tumors beyond the supraclavicular areas (FIGURE).¹Researchers are looking to unique immunotherapy combinations, including chemotherapy, PARP inhibitors in monotherapy and in combination, and potential biomarkers that can lead to personalized treatment based on tumor cell expression to improve outcomes for these patients.Current treatment protocols for LS-SCLC include chemotherapy with etoposide and cisplatin, along with thoracic radiation therapy.1 In cases of early disease, generally confined to small tumors without mediastinal lymph node involvement, the conventional approach is surgical resection followed by systemic therapy.^1-3

In the ES-SCLC setting, the standard treatment includes chemotherapy with platinum plus etoposide, with a general preference for carboplatin over cisplatin.^2,3However, when the National Comprehensive Cancer Network guidelines were updated in March 2019, it recommended the addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to combination chemotherapy as first-line treatment, followed by maintenance atezolizumab.³This updated recommendation was based on results from the IMpower133 trial.⁴In this study, patients with previously untreated ES-SCLC were given atezolizumab or placebo along with platinum and etoposide combination chemotherapy, which was followed by atezolizumab maintenance therapy (if they had received atezolizumab already) or placebo. Those receiving atezolizumab demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) than patients receiving placebo. Response rates were similar—60% with chemotherapy plus atezolizumab and 64% with chemotherapy alone—but adding atezolizumab resulted in significantly longer median OS (HR for death, 0.70; 95% CI, 0.54-0.91; P = .007). Rates of grade 3 or 4 adverse events were similar in both groups (56% for both).

Overall, SCLC is very responsive to first-line treatment; however, relapses are generally more resistant to treatment. Even with systemic therapy, median survival in relapsed disease is only 4 to 5 months.³Treatment depends on the time from initial therapy to relapse. If the interval is less than 3 months, response is ≤10%. If patients relapse more than 3 months after therapy, response rates are approximately 25%. If more than 6 months have passed at relapse after first-line therapy, treatment with the original regimen is recommended, although if the patient received atezolizumab plus chemotherapy and is on maintenance therapy at the time of relapse, they should only receive chemotherapy.

Recently, immune checkpoint inhibitors (ICIs), including nivolumab (Opdivo) with or without ipilimumab (Yervoy) and pembrolizumab (Keytruda), have been added as options for subsequent therapy in patients with SCLC.³The CheckMate 032 study was designed to compare nivolumab alone with various doses of nivolumab plus ipilimumab for relapsed SCLC, and demonstrated higher response rates for the combination treatments.5 Follow-up data revealed a 1-year OS of 42% in patients receiving the combination of nivolumab plus ipilimumab versus 30% in those receiving nivolumab alone. Although PD-L1 expression correlates to response in non—small cell lung cancer (NSCLC), responses in SCLC do not correlate with PD-L1 expression. There is evidence that tumor mutation burden (TMB) may be useful as a biomarker for SCLC, but further assessment is needed.⁶

In 2019, pembrolizumab was added as a subsequent therapy option for patients with SCLC regardless of PD-L1 levels.³In the KEYNOTE-028 and KEYNOTE-158 studies, the response rate was 19.3%, with a median OS of 7.7 months.⁷Also in both studies, OS and response rates were higher in patients with PD-L1—positive histology. Therefore, PD-L1 and TMB may be useful biomarkers in SCLC when selecting subsequent therapies.

Data from immune checkpoint blockade (ICB) combinations demonstrate that although this class of agents is effective, only a small percentage of patients respond.⁸

PARP Inhibitors and Potential Biomarkers

“[Although] the use of immunotherapy has revolutionized the way we treat lung cancer, we find that small cell lung cancers can escape the immune system very effectively, so we see a much lower response rate,” said Lauren Averett Byers, MD, associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, in a news release.⁹“However, we want to do a lot better for our patients, and we think there’s a lot of room for further improvement.”SCLC is highly responsive to DNA-damaging agents used in combination, which may be related to the genetic changes within the tumor cells during oncogenesis.¹⁰Because of this sensitivity to DNA damage displayed by SCLC, targeting DNA repair pathways is a logical strategy to improve treatment protocols. PARPs detect DNA single-strand breaks and recruit appropriate repair complexes to repair the break. PARP inhibitors have 2 mechanisms, enzymatic inhibition and PARP trapping, where the inhibitor/PARP complex becomes fixed on the DNA, inducing multiple double-strand breaks during replication.

“We predicted that if we combined PARP inhibitors or other drugs that cause DNA damage with immune therapies, we might see a much greater response to the immune therapy,” explained Byers. Using PARP inhibitors in combination with ICIs is a reasonable strategy, because DNA damage response inhibition may sensitize cells to ICB.⁸In breast cancer and non— small cell lung cancer, treatment with PARP inhibitors increased expression of PD-L1. The DNA damage done by PARP inhibitors increases cytosolic DNA, which activates intracellular mechanisms leading to T-cell recruitment and increased PD-L1 expression. Similar action has been demonstrated following combination therapy in murine models, where either olaparib (Lynparza) or prexasertib, an inhibitor of checkpoint kinase 1 (CHK1), combined with an anti– PD-L1 therapy led to increased PD-L1 expression and cytotoxic T-cell infiltration, decreased T-cell exhaustion, and regressed tumors.

In a phase II study of olaparib combined with durvalumab (Imfinzi) in relapsed SCLC, the overall response rate (ORR) was only 10.5%, although clinical benefit was shown in 21.1% of patients. This trial also presented data suggesting an association between an inflamed microenvironment and response.⁸Overall, 2 patients with inflamed phenotypes, defined as CD8-positive T cells in direct contact with the tumor, had confirmed responses to the therapy.¹¹

A combination of olaparib and temozolomide (Temodar) resulted in an ORR of 41.7% in patients with relapsed SCLC.¹²Patients had received a median of 2 prior treatments (range, 1 to 7). Therapy included olaparib and temozolomide on the first 7 days of each 21-day cycle, given until disease progression or toxicity. PFS was 4.2 months and median OS was 8.5 months.

“We found that if we added either PARP or CHK1 inhibitors to immunotherapy, we saw a dramatic shrinkage of tumors,” Byers, the corresponding author of the study, said. “In fact, in some cases, the tumors disappeared completely.”

“I think the results from this study are compelling, because of the dramatic activity that we saw with the combination of adding a targeted therapy to immune therapy,” Byers added. “I think our findings can be rapidly translated into the clinic for our patients and to other cancer types.”

A coclinical trial in patient-derived xenograft (PDX) models evaluated predictive biomarkers, and 4 inflammatory response genes were found to be potential indicators for response: CEACAM1, TNFSF10, TGIF1, and OAS1.¹²Resistance to first-line chemotherapy and the combination of olaparib/temozolomide was linked to low basal expression of these biomarkers.

SLFN11 as a Potential Biomarker

Biomarkers associated with improved response with ICI therapy in SCLC, including TMB, PD-L1 expression, and inflamed immune phenotypes, warrant further evaluation. Findings from several studies have suggested the Schlafen family member 11 protein (SLFN11) could be a potential biomarker in SCLC, warranting consideration of future investigations, including SLFN11 in PARP inhibitor/ICI combinations.⁵SLFN11 has been shown to predict sensitivity to platinum chemotherapy and topoisomerase inhibitors, and is a candidate as a biomarker for PARP inhibitors.¹³In a study comparing combination veliparib and temozolomide to temozolomide monotherapy, patients with recurrent SCLC were assigned 1:1 to receive oral veliparib or placebo 40 mg twice daily on days 1 to 7 and oral temozolomide 150 to 200 mg/m2/day on days 1 to 5 of a 28-day cycle.¹⁴Treatment continued until disease progression, adverse effects, or withdrawal of consent. The primary endpoint was improvement in PFS at 4 months, and secondary endpoints were ORR, OS, safety, and tolerability. Immunohistochemical expression of PARP-1 and SLFN11 was evaluated.

Results showed no significant difference between temozolomide/veliparib and temozolomide/placebo for 4-month PFS (36% vs 27%; P = .19).¹⁴Median OS also did not show a significant difference between groups. However, ORR was higher in patients receiving temozolomide/veliparib compared with temozolomide/ placebo (39% vs 14%; P = .016). Patients with SLFN11-positive tumors treated with temozolomide/veliparib had significantly prolonged PFS and OS compared with those receiving the combination with SLFN11-negative tumors.

Findings from a study evaluating SFLN11 in vitro and in PDX models support SLFN11 as a potential biomarker in SCLC.¹⁰SFLN11 cell lines were created using gene editing techniques, including a short hairpin RNA micro- RNA-E sequence and knockout by CRISPR/ Cas9 through the design of single-guide RNAs targeting SLFN11. Cell cultures were treated with talazoparib (Talzenna) and evaluated with specific detection protocols. SCLC cell lines with high levels of transcript were determined to be more sensitive to PARP inhibitors and cytotoxic therapies. Removing SLFN11 confirmed that loss of SLFN11 confers resistance to talazoparib.

SLFN11 expression is associated with tumor response to talazoparib in xenograft models. The in vivo portion of the study evaluated SLFN11 expression with mouse PDX models.¹⁰Testing in PDXs has been shown to better approximate human responses than experiments conducted in cell lines. Of the 7 models, the 3 considered high in SLFN11 demonstrated tumor growth inhibition with talazoparib. None of the SLFN11- low models responded to talazoparib. When investigating the combination of talazoparib and temozolomide, the combination exhibited significantly greater tumor growth inhibition than treatment with single agents.

SLFN11 was highly expressed in SCLC compared with other histologies, such as breast cancer and glioblastoma.¹⁰The bimodal distribution of SLFN11 gene expression may be used as a predictive biomarker to provide stratification in future clinical trials of SCLC.

Recent additions to treatment options for patients with SCLC show promise, although long-term survival after diagnosis remains low. When included as part of first-line management, ICI therapy can improve outcomes in some patients. PARP inhibitors also show promise as SCLC treatment options, particularly in combination with an ICI. When available, biomarkers are useful for predicting response and selecting appropriate patients. Based on preliminary data, further testing of SLFN11 as a biomarker in patients with SCLC treated with PARP inhibitor therapy is warranted.

References:

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8. Gay CM, Byers LA. PARP inhibition combined with immune checkpoint blockade in SCLC: oasis in an immune desert or mirage?J Thorac Oncol. 2019;14(8):1323-1326. doi: 10.1016/j.jtho.2019.05.004.
9. University of Texas MD Anderson Cancer Center. Preclinical research finds new approach to treating aggressive cancer. Medical Xpress website. medicalxpress.com/news/2019-02-preclinical-approach-aggressive-cancer.html. Published February 18, 2019. Accessed October 15, 2019.
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11. Ott PA, Bang YJ, Piha-Paul SA, et al. T-cell-inflamed gene-expression profile, programed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028.J Clin Oncol. 2019;37(4):318-327. doi: 10.1200/JCO.2018.78.2276.