Home Therapeutic relationship YAP1, inflamed T-cell subtypes linked to enhanced Durvalumab/chemo responses in ES-SCLC

YAP1, inflamed T-cell subtypes linked to enhanced Durvalumab/chemo responses in ES-SCLC

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Patients with extensive stage small cell lung cancer (ES-SCLC) whose disease harbors inflamed T cells or YAP1 according to an exploratory analysis of the Phase 3 CASPIAN study (NCT03043872) which was recently presented at the AACR 2022 Annual Meeting.1

An analysis of 2 different RNA sequencing-based SCLC subtyping methods applied in the context of CASPIAN data demonstrated that patients with these subtypes experienced the longest OS after treatment with the combination of immunotherapy compared to patients expressing POU2F3, NEUROD1, and ASCL1.

Overall, the highest median OS was observed in patients YAP1 or Expression of the inflamed T-cell signature who received durvalumab/EP. In these patients, the median OS was 17.3 months (95% CI, 12.8-NE) and 17.6 months (95% CI, 11.4-NE), respectively.

These data are consistent with previous findings, although further research is warranted to determine the relationship between these biomarkers and immunotherapeutic response, the study authors noted.

“When the 2 RNA-based subtyping methods were applied to CASPIAN data, we found that the 2 methods were consistent in differentiating neuroendocrine from non-neuroendocrine subtypes, and showed the greatest concordance in non-neuroendocrine subtypes,” said study lead author Yashaswi Shrestha. , PhD, director of oncology translational medicine and clinical biomarkers at AstraZeneca, said during a presentation of the results. “Of the 4 subtypes, the inflamed subtype determined by Gay et al and the YAP1 subtype [determined] by Rudin et al showed the longest overall survival in durvalumab/[chemotherapy] arm, suggesting that [this] subset of patients who have an inflamed phenotype are primed to respond to immunotherapy.

CASPIAN Phase 3 researchers enrolled 805 patients with treatment-naïve SCLC-ES and a World Health Organization performance status of 0 or 1, life expectancy 12 weeks or more and measurable disease according to RECIST v1.1 criteria. Patients with asymptomatic or treated and stable brain metastases were allowed to enroll.2

Enrolled patients were randomized 1:1:1 to receive either durvalumab plus etoposide with carboplatin or cisplatin (EP) for 4 cycles followed by durvalumab monotherapy until disease progression, EP up to 6 cycles followed by optional prophylactic cranial irradiation, or tremelimumab added to durvalumab plus EP for 4 cycles, followed by durvalumab until disease progression.

EP was administered at a dose ranging from 80 to 100 mg/m2 of etoposide with either the area under the carboplatin curve 5-6 or 75-80 mg/m2 of cisplatin. Durvalumab was administered at 1500 mg and tremelimumab was administered at 75 mg.

The CASPIAN co-primary endpoints were OS; progression-free survival, overall response rate, safety and tolerability, and patient-reported outcomes (PRO) were secondary endpoints. Biomarker analysis (tTMB; PD-L1) was an exploratory outcome measure.

Previous CASPIAN results revealed that durvalumab/EP significantly improved OS compared to EP alone in this patient population, a benefit that was sustained over more than 3 years of median follow-up. In the intent-to-treat population, the median OS was 12.9 months (95% CI, 11.3-14.7) with durvalumab/EP and 10.5 months (95% CI, 9.3 -11.2) with EP alone (HR, 0.71; 95% CI, 0.60-0.86; P = .0003).

These results established durvalumab/EP as the global standard of care in ES-SCLC.2 The combination is FDA-approved for the first-line treatment of patients with ES-SCLC.

Notably, the association between predictive biomarkers and improved outcomes with immune checkpoint inhibitors is still not well understood for patients with SCLC. However, researchers recently identified 4 SCLC molecular subtypes with distinct therapeutic vulnerabilities using 2 different differential gene expression methods.3.4

Investigators in the exploratory analysis therefore assessed the concordance between the 2 methods and their association with improved OS using RNA sequencing data from the Phase 3 CASPIAN study.

Formalin-fixed, paraffin-embedded (FFPE) tumor samples previously collected at baseline were used to create whole-transcriptome RNA sequencing data.

Overall, the biomarker-evaluable (BEP) population consisted of 57 of 268 patients on durvalumab/EP and 47 of 269 patients on EP monotherapy arms.

For the BEP population, the data cut-off date was March 2021, and the median number of months of follow-up was 39.4 months (range, 0.1 to 47.5). In the BEP population, the median OS was 11.8 months (95% CI, 8.6-14.9) with durvalumab/EP and 9.1 months (95% CI, 7.7-11, 3) with EP alone (HR, 0.61; 95% CI, 0.40-0.92).

Le Rudin et al. The SCLC 20193 subtyping method revealed that YAP1 was commonly expressed in all subtypes, although at a relatively low level. Therefore, a sample was labeled as YAP1 if the YAP1 expression was greater than ASCL1, NEUROD1, and PUO2F3. Of the 4 transcription factors determined to be a sample subtype, ASCL1 and NEUROD1 have been classified as neuroendocrine while POU2F3 and YAP1 devoid of neuroendocrine markers.

Le Gay et al. The 20214 SCLC subtyping method used a genetic signature of 1300 to organize the subtypes into 4 hierarchical groups, each of which was assigned a subtype based on the most expressed gene of ASCL1, ODNUM1and POU2F3. The fourth group, which showed low expression of all 3 genetic signatures, was designated as the inflamed subtype due to its inflamed genetic signature.

The inflamed T-cell signature was identified through the evaluation of basal RNA tumor samples from patients treated with pembrolizumab (Keytruda). The 18-gene inflamed T cell gene expression signature included IFN-γ responsive genes linked to antigen presentation, chemokine expression, cytotoxic activity and immune resistance adaptive.

The methods revealed high agreement in distinguishing neuroendocrine tumors from non-neuroendocrine subtypes. The highest levels of concordance were identified between non-neuroendocrine subtypes: the prevalence of Rudin YAP1 was 8% and the prevalence of homosexual inflammation was 11%.

An OS analysis of the Rudin et al method revealed that, among patients treated with durvalumab/EP, the median OS with ASCL1 markers was 11.5 months, NEUROD1 was 9.5 months, POU2F3 was 4.8 months, and YAP1 was 17.3 months. In patients treated with EP alone, the median OS with ASCL1 markers was 10.7 months, NEUROD1 was 7.1 months, POU2F3 was 6.1 months, and YAP1 was 6.9 months.

An analysis by Gay et al. showed that, among patients treated with durvalumab/EP, the median OS with ASCL1 markers was 9.5 months, NEUROD1 was 14.6 months, POU2F3 was 6.8 months, and YAP1 was 17.6 months. In patients treated with EP alone, the median OS with ASCL1 was 8.3 months, NEUROD1 was 10.5 months, POU2F3 was 7.5 months, and YAP1 was 11.3 months.

Specifically, patients with a high T-cell inflammatory signature had numerically longer OS when receiving durvalumab/EP treatment than with EP alone. Patients in the first group had a median upper quartile OS of 15.8 months (10.4-NE) and a median low OS of 11.3 months (7.3-14.6; HR, 0.64; CI at 95%, 0.31-1.32). Patients receiving PE alone had a median upper quartile OS of 9.4 months (95% CI, 7.3-15.9) and a median low OS of 8.3 months (95% CI, 6. 1-11.4), resulting in a 13% reduction in the risk of disease progression or death (HR, 0.87; 95% CI, 0.45-1.66).

“This finding is consistent with previous observations,” Shrestha concluded. “[However]further analysis is needed so that we can gain confidence in response and resistance biomarkers for immunotherapy and small cell lung cancer.

Due to the limited sample size of eligible RNA sequencing data, these findings should be considered hypothesis-generating, Shrestha noted.

References

  1. Xie M, Chugh P, Broadhurst H, et al. Durvalumab + platinum-etoposide in extensive stage small cell lung cancer (ES-SCLC): exploratory analysis of SCLC molecular subtypes in CASPIAN. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT024.
  2. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in the first-line treatment of extensive-stage small cell lung cancer (CASPIAN): randomized, controlled, open-label phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6.
  3. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of data from human and mouse models [published correction appears in Nat Rev Cancer. June 7, 2019]. Nat Rev Cancer. 2019;19(5):289-297. doi: 10.1038/s41568-019-0133-9.
  4. Gay CM, Stewart CA, Park EM, et al. Models of transcription factor and activating immune pathway programs define four major subtypes of SCLC with distinct therapeutic vulnerabilities. cancer cell. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014.