Durvalumab + Olaparib for Non-Small Cell Lung Cancer

(ORION Trial)

Recruiting at 64 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must be taking: Platinum-based chemotherapy

Must not be taking: Immunosuppressive, Chemotherapy, PARP therapy

Disqualifiers: Autoimmune disorders, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

401 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of two drugs, Durvalumab and Olaparib, against using just Durvalumab alone. It targets adults with advanced lung cancer that cannot be treated with surgery or radiation and lacks certain genetic mutations. Durvalumab helps the immune system attack cancer, while Olaparib prevents cancer cells from repairing themselves. Durvalumab is a standard drug used after initial treatment in patients with advanced non-small cell lung cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use any chemotherapy, biologic, or hormonal therapy for cancer treatment, or immunosuppressive medication within 14 days before starting the trial.

What data supports the effectiveness of the drug combination Durvalumab and Olaparib for treating non-small cell lung cancer?

Durvalumab has been shown to improve survival in non-small cell lung cancer when used after chemoradiation, and combining it with Olaparib has shown antitumor activity in breast cancer studies. This suggests potential effectiveness in lung cancer, although direct evidence for this specific combination in lung cancer is not yet available. ^{1 2 3 4 5}

Is the combination of Durvalumab and Olaparib safe for humans?

The combination of Durvalumab and Olaparib has been studied in various cancers and is generally considered tolerable, with no dose-limiting toxicities reported in some studies. However, some patients experienced immune-related side effects, such as fatigue and hypertension (high blood pressure). ^{1 2 5 6 7}

How is the drug combination of Durvalumab and Olaparib unique for treating non-small cell lung cancer?

The combination of Durvalumab and Olaparib is unique because it combines an immune checkpoint inhibitor (Durvalumab) that helps the immune system attack cancer cells, with a PARP inhibitor (Olaparib) that targets cancer cell DNA repair mechanisms, potentially enhancing the overall treatment effect compared to using either drug alone. ^{2 3 8 9 10}

Research Team

Myung-Ju Ahn, MD

Principal Investigator

Sungkyunkwan University School of Medicine, 135-710, Seoul, Korea

Eligibility Criteria

This trial is for Stage IV non-small cell lung cancer patients without certain genetic mutations, who've had no prior systemic therapy and responded to initial chemo with Durvalumab. They must be able to perform daily activities with little or no assistance, swallow pills, and have proper kidney function and organ health.

Inclusion Criteria

I have not received any treatment for stage IV non-small cell lung cancer.

I can swallow pills whole.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

My lung cancer is a mix of small-cell and sarcomatoid types.

I am not currently on any cancer treatments like chemotherapy or hormone therapy.

I haven't taken immunosuppressive drugs in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Therapy

Patients receive Durvalumab along with the Investigator's choice of platinum-based doublet therapy for 4 cycles

8-12 weeks

Maintenance Therapy

Patients receive either Durvalumab plus placebo or Durvalumab plus Olaparib until disease progression or unacceptable toxicity

Up to 18 months

Follow-up

Participants are monitored for survival and disease progression

Up to 18 months

Treatment Details

Interventions

• Durvalumab
• Olaparib

Trial Overview The ORION study tests if adding Olaparib to Durvalumab maintenance therapy is more effective than Durvalumab alone after initial chemo in advanced lung cancer patients. It's a global Phase II trial where participants are randomly assigned treatment options in a blinded manner.

Participant Groups

Group I: Durvalumab/Olaparib Combination Therapy Experimental Treatment 7 Interventions

Durvalumab/Olaparib Combination Therapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/Olaparib (maintenance phase)

Group II: Durvalumab Monotherapy Experimental Treatment 7 Interventions

Durvalumab Monotherapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/placebo (maintenance phase)

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[2021]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In a study of 421 patients with stage III nonsmall-cell lung cancer (NSCLC) who completed chemoradiation, 76.5% initiated adjuvant durvalumab, indicating a strong uptake of this treatment in real-world settings.

The initiation of adjuvant durvalumab increased significantly over time, from 66% to 92%, suggesting that it has been rapidly integrated into clinical practice, particularly among patients with better performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer. Bryant, AK., Yin, H., Schipper, MJ., et al.[2023]

The combination of durvalumab (a PD-L1 inhibitor) and olaparib (a PARP inhibitor) with standard paclitaxel chemotherapy significantly increased pathologic complete response (pCR) rates in stage II/III HER2-negative breast cancer, with rates rising from 20% to 37% overall.

While DOP showed enhanced efficacy, particularly in high-risk hormone receptor-positive/HER2-negative patients (pCR 64% vs. 22%), it also resulted in a higher incidence of immune-related grade 3 adverse events (12.3% vs. 1.3% in the control group).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Pusztai, L., Yau, C., Wolf, DM., et al.[2023]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

In a phase I study involving 26 women with recurrent cancers, the combination of the PD-L1 inhibitor durvalumab with olaparib or cediranib was found to be tolerable and showed promising anti-tumor activity, with an 83% disease control rate for the durvalumab plus olaparib group.

The recommended phase II doses were established as durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice daily, or cediranib 20 mg on an intermittent schedule, indicating that these combinations could be viable options for further investigation in treating recurrent women's cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. Lee, JM., Cimino-Mathews, A., Peer, CJ., et al.[2022]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Durvalumab has been approved for use in patients with locally advanced PD-L1-positive non-small cell lung cancer (NSCLC) after chemoradiotherapy, based on its efficacy demonstrated in the PACIFIC trial and subsequent analysis of 211 patients in the Expanded Access Program (EAP).

In the EAP, 126 patients who received durvalumab were included, some of whom had oligometastatic disease and a history of autoimmune conditions, indicating that durvalumab may be effective and safe for a broader patient population than previously studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. Faehling, M., Schumann, C., Christopoulos, P., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Presurgery Plus Postsurgery Immunotherapy Ups Survival in NSCLC. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. [2020]