P1.15-004 An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC

Krebs, Matthew; Ross, Kirsty; Kim, S.; Jonge, Maja de; Postel-Vinay, Sophie; Domchek, Susan M.; Lee, J.; Angell, Helen K.; Bui, Kieu-Thu; Chang, Shu‐Wen; Gresty, Christopher; Herbolsheimer, Pia; Delord, Jean Pierre

doi:10.1016/j.jtho.2017.09.1040

Cited by 31 publications

(26 citation statements)

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“…However, these increases failed to correlate with T-cell infiltration. The disappointing response rates in this trial are similar to a previous phase II basket study including patients with relapsed SCLC that used the same doses of olaparib and durvalumab but with a 4-week olaparib run-in period [66]. These early results suggest that additional mechanisms suppress antitumor immunity in SCLC.…”

Section: Combining Parp and Immune Checkpoint Inhibitionsupporting

confidence: 70%

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

Knelson

Patel

2021

Cancers

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Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality.

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Section: Combining Parp and Immune Checkpoint Inhibitionsupporting

confidence: 70%

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

Knelson

Patel

2021

Cancers

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“…Differences in the immune phenotype across the molecular aberrations, such as BRCA1, BRCA2, and mutations in the homologous recombination repair pathway, are known to infer response to PARPi. Such detailed understanding is required to predict to what extent PARP inhibitors may enhance response to immune checkpoint blockade, such as PD-L1 (50)(51)(52)(53), or other immunotherapy approaches.…”

Section: Adapting Clinical Trials Design For Immunotherapymentioning

confidence: 99%

The Immunoscore: Colon Cancer and Beyond

Angell

Bruni

Barrett

et al. 2020

Clinical Cancer Research

291

249

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Tumors evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumor and the host immune system. Clinical trials have shown that appropriate enhancement of a tumor immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumor indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumor-immune interaction, the spatiotemporal interplay of numerous different immune cell types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment. In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high risk of tumor recurrence will be discussed. The Immunoscore may translate to provide a tumor agnostic method to define immune fitness of a given tumor and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.

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“…A phase II trial of durvalumab in combination with olaparib for selected advanced solid cancers (MEDIOLA) showed that this combination is well tolerated with no significant overlapping toxicities (108)(109)(110)(111). Clinical response measured as disease control rate at 12 weeks was 29%, 80%, and 81% in patients with advanced SCLC, germline BRCA1/2-mutant HER2-normal breast cancer, and germline BRCA1/2-mutant platinum-sensitive ovarian cancer, respectively (109)(110)(111). This same combination was also assessed in patients with CRPC, and reported a 12-month PFS of 51% in a population unselected for DDR variants (112).…”

Section: Immune Checkpoint Inhibitor Combinationsmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

271

206

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A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."

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P1.15-004 An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC

Cited by 31 publications

References 0 publications

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

The Immunoscore: Colon Cancer and Beyond

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

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