The recent update on the Phase II TRINITY clinical trial (NCT02674568) of AbbVie’s rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting the cancer-stem cell-associated delta-like protein 3 (DLL3) in relapsed/refractory (R/R) small cell lung cancer (SCLC) provided a major blow to AbbVie’s plans to seek an accelerated FDA approval for Rova-T in this notoriously difficult-to-treat lung cancer.

The significance of the TRINITY trial lies in the fact that it is the first biomarker-based clinical study in SCLC. DLL3 is expressed in more than 80% of SCLC patient tumours but not in healthy tissue, making it a ubiquitous tumour-specific biomarker for SCLC. Assessment of Rova-T as a single agent and in a highly pretreated patient population could explain why the updated results were weaker than anticipated yet do not rule out a role for DLL3 as a predictive biomarker for response in SCLC. DLL3 could still prove its worth in earlier treatment settings and predict response to combination regimens of Rova-T as well as other novel therapies and the discouraging news should be all the more reason to foster the search for other biomarkers in a heterogenous disease like SCLC where there is a lack of predictive biomarkers.

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Additional biomarkers in SCLC

To this end, this year’s AACR meeting provided exciting preliminary data for additional therapeutic biomarkers in SCLC. One of the hallmarks of SCLC is the universal loss of TP53 and RB1, which have essential roles in protecting genomic integrity by way of regulating DNA replication and damage repair. Consequently, DNA damage response proteins such as PARP1, Chk1, ATM, and ATR are highly expressed in SCLC and are potential targets with anticipated therapeutic value in this setting.

Despite the strong rationale, the available clinical efficacy data of PARP inhibitors (PARPis) Lynparza (olaparib), veliparib, and talazoparib has been modest in SCLC compared to that seen in breast or ovarian cancer. Notably, in preclinical mouse models of patient derived tumour cells, it was shown that expression of SLFN11, which is correlated with response to chemotherapy and is substantially lower in chemo-resistant samples, was higher in xenografts that responded to talazoparib.

More encouraging was confirmation of the predictive role of SLFN11 in R/R SCLC patients who were treated with veliparib or veliparib + temozolomide in the randomized Phase II trial (NCT01638546). In the unselected patient cohorts, progression-free survival and overall survival (OS) were comparable upon treatment with veliparib + temozolomide or temozolomide. However, when SLFN11 expression was accounted for retrospectively in the combination cohort, expressers derived significantly higher clinical benefit compared to non-expressers (median OS = 12.2 months versus 7.5 months; p = 0.014). On the other hand, expression of SLFN11 did not correlate with clinical benefit in the temozolomide monotherapy cohort, which indicated that the correlation is specific to PARP inhibition by veliparib.

Although the available evidence from the studies of two different PARP inhibitors is an encouraging indicator for the role of SLFN11 as a predictive biomarker in SCLC, the retrospective observations need to be validated in prospective biomarker-based clinical studies. It is estimated that approximately half of SCLC patients express SLFN11 in their tumours. Therefore if confirmed in prospective clinical trials, a sizable proportion of SCLC patients will be eligible for treatment with PARPis and have improved therapeutic outcome.

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GlobalData (2017). PharmaFocus: Visual Analysis of Immuno-Oncology Development and Opportunities, August 2017, GDHC009PFR.

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