Updated results from the PACIFIC Phase III trial confirmed that durvalumab (previously known as MEDI4736; Imfinzi®; AstraZeneca) demonstrated a sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT).

The PACIFIC trial was a Phase III, randomized, double-blinded, placebo-controlled, multi-center trial of durvalumab as a treatment in all-comer patients, regardless of PD-L1 status, with unresectable, Stage III NSCLC whose disease had not progressed following concurrent platinum-based CRT. The trial was conducted at 235 centers across 26 countries involving 713 patients. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate (ORR), and duration of response (DoR).

Overall, one in three patients with NSCLC is diagnosed at Stage III, where the majority of tumors are unresectable. [1][2] Prior to the approval of durvalumab in this setting, no new treatments beyond concurrent chemoradiation therapy had been available to these patients for decades. [3][4][5]

Photo: Corinne Faivre-Finn, FRCR, M.D., Ph.D., Professor at The University of Manchester and The Christie NHS Foundation Trust, and a lead investigator in the PACIFIC Phase III trial. Photo courtesy: © 2020 ESMO. Ised with permission.

Updated analyses
The results from the updated posthoc analyses confirmed an estimated four-year overall survival rate of 49.6% for durvalumab versus 36.3% for placebo after CRT. Median OS was 47.5 months for patients treated with durvalumab versus 29.1 for placebo. With a maximum treatment course of one year, an estimated 35.3% of patients treated with durvalumab had not progressed four years after enrollment versus 19.5% for placebo. These data build on published in The New England Journal of Medicine demonstrating a significant benefit for durvalumab in the OS primary endpoint.[6]

“Previously, only 15 to 30% of patients with unresectable, Stage III non-small cell lung cancer survived five years, and the majority eventually progressed to metastatic disease,” noted Corinne Faivre-Finn, FRCR, M.D., Ph.D., Professor at The University of Manchester and The Christie NHS Foundation Trust, and a lead investigator in the PACIFIC Phase III trial.

“These data show about half of the patients treated with durvalumab survived four years, and an estimated 35% had not progressed, a remarkable advance in this curative-intent setting,” she added.

Photo: José Baselga, M.D., Ph.D., Executive Vice President, Oncology R&D at AstraZeneca. Photo courtesy: 2018 American Association for Cancer Research (AACR) © 2018. Used with permission.

Unprecedented results
“These unprecedented four-year results reinforce durvalumab as the established standard of care in unresectable, Stage III non-small cell lung cancer and set a new survival benchmark in a setting where cure is the treatment goal,”  said José Baselga, M.D., Ph.D., Executive Vice President, Oncology R&D at AstraZeneca.

“With data also [presented] at the European Society for Medical Oncology (ESMO) Virtual Congress for CASPIAN in small cell lung cancer patients, durvalumab continues to deliver impressive long-term benefits across different types of lung cancer,” Baselga added.

In the primary OS analysis of the PACIFIC Phase III trial, the most common adverse events (AE) (greater than or equal to 20%) among patients treated with durvalumab versus placebo were cough (35.2% versus 25.2%), fatigue (24.0% versus 20.5%), dyspnea (22.3% versus 23.9%) and radiation pneumonitis (20.2% versus 15.8%). A grade 3 or 4 AE was experienced by 30.5% of patients treated with durvalumab versus 26.1% for placebo, and 15.4% of patients discontinued treatment due to adverse events with durvalumab versus 9.8% for placebo.

CASPIAN Phase III trial
In addition to PACIFIC Phase III trial, new exploratory subgroup analyses from the CASPIAN Phase III trial, of durvalumab showed long-term benefits.

The CISPIAN trial was a randomized, open-label, multi-center, global, Phase III trial in the 1st-line treatment of patients with extensive-stage small-cell lung cancer (SCLC) and compared durvalumab in combination with etoposide and either cisplatin or carboplatin chemotherapy, or durvalumab, tremelimumab, and chemotherapy versus chemotherapy alone.

The analyses showed that more than three times as many patients treated with durvalumab plus chemotherapy were alive and progression-free for one year or more (PFS ≥12 months) versus chemotherapy alone (17% versus 4.5%). Across all treatment arms, the subgroup of patients who were progression-free at one year had a 75% chance of being alive at two years. In comparison, the subgroup of patients whose disease had progressed within one year (PFS <12 months) had a 10% chance of being alive at two years. Clinical characteristics did not appear to identify patients who derived long-term benefits.

Patients with PFS ≥12 months received more cycles of durvalumab treatment compared to patients with PFS <12 months (median of 25 cycles versus 7). Although patients with greater exposure to durvalumab had numerically higher rates of immune-mediated adverse events, the two subgroups had similar rates of severe AEs, serious AEs and AEs leading to discontinuation.

The CASPIAN trial met the primary endpoint of OS in 2019, reducing the risk of death by 27% in patients with ES-SCLC treated with durvalumab plus a choice of chemotherapy versus chemotherapy alone. The safety and tolerability of durvalumab plus chemotherapy were consistent with the known safety profiles of these medicines. These results were published in The Lancet in 2019 and formed the basis of regulatory approvals around the world.[7]

Leading cause of cancer death
Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths.[8] Lung cancer is broadly split into NSCLC and SCLC, with about 85% classified as NSCLC and 15% classified as SCLC [9]

Stage III NSCLC (locally advanced) is commonly divided into three sub-categories (IIIA, IIIB, and IIIC), defined by how much cancer has spread locally and the possibility of surgery. [10] Stage III disease is different from Stage IV disease, when cancer has spread (metastasized), as the majority of Stage III patients are treated with curative intent.[10][11]

In 2015, Stage III NSCLC was estimated to affect nearly 200,000 patients in the following eight key countries: China, France, Germany, Italy, Japan, Spain, UK, and the US, with approximately 43,000 cases in the US alone.[2]

Small-cell lung cancer is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly, despite initial response to chemotherapy. [12][13] About two-thirds of SCLC patients are diagnosed with extensive-stage disease, in which cancer has spread widely through the lung or to other parts of the body. [14] Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis. [14]

Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses. The drug is approved by the U.S. Food and Drug Administration and other regulatory bodies in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy.

Results from the PACIFIC and CASPIAN Phase III trials were presented during the ESMO Virtual Congress on September 19 and September 21, 2020.

Clinical trials
A Study of Durvalumab as Consolidation Therapy in Non-Small Cell Lung Cancer Patients (PACIFIC-5) – NCT03706690
A Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC) – NCT02125461
Durvalumab ± Tremelimumab in Combination With Platinum-based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer (CASPIAN) (CASPIAN) – NCT03043872

Highlights of prescribing information
Durvalumab (Imfinzi®; AstraZeneca)[Prescribing Information]
Etoposide (Etopophos®; Bristol-Myers Squibb)[Prescribing Information]
Cisplatin (Platinol-AQ®)[Prescribing Information]]
Carboplatin [Paraplatin®; Bristol-Myers Squibb)[Prescription Information]

Reference
[1] Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
[2] Kantar Health CancerMPact. Treatment Modality. Online. Last accessed on September 14, 2020.
[3] Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410 [published correction appears in J Natl Cancer Inst. 2012 Jan 4;104(1):79]. J Natl Cancer Inst. 2011;103(19):1452-1460. doi:10.1093/jnci/djr325
[4] NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8. 2017 Aug 3.
[5] Hanna N, et al. Current Standards and Clinical Trials in Systemic Therapy for Stage III Lung Cancer: What is New? Am Soc Clin Oncol Educ Book. 2015;e442-447.
[6] Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697
[7] Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
[8] American Cancer Society. Key Statistics for Lung Cancer. Online Online. Last accessed on September 14, 2020.
[9] American Cancer Society. What is Lung Cancer? Available at Online. Last accessed September 14, 2020.
[10] ASCO. Cancer.net. Lung Cancer – Non-Small Cell. Online. Online. Last accessed September 14, 2020.
[11] Cheema PK, Rothenstein J, Melosky B, Brade A, Hirsh V. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42. doi:10.3747/co.25.4096
[12] Qin A, Kalemkerian GP. Treatment Options for Relapsed Small-Cell Lung Cancer: What Progress Have We Made?. J Oncol Pract. 2018;14(6):369-370. doi:10.1200/JOP.18.00278
[13] National Cancer Institute. NCI Dictionary – Small Cell Lung Cancer. Online. Available at Online. Last accessed on September, 14 2020.
[14] Cancer.Net. Lung Cancer – Small Cell. Online. Online. Last accessed September 14, 2020.
[15] Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018;3(15):e120858. Published 2018 Aug 9. doi:10.1172/jci.insight.120858

Featured image: ESMO annual meeting 2018. Photo courtesy: © 2018 European Society for Medical Oncology. Used with permission

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