A local case sharing of an enhanced prognosis with durvalumab in non-small-cell lung cancer
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide.1 According to European Society for Medical Oncology (ESMO) 2017 guidelines, recommended treatment for unresectable stage III NSCLC is concurrent CRT.2 Still, the incidence of relapses is high and additional therapies are needed to enhance the overall survival (OS). However, in the recent National Comprehensive Cancer Network (NCCN) guidelines, the standard of care includes durvalumab following concurrent CRT.3 As shown in the PACIFIC trial, durvalumab, the first and only immunotherapy, demonstrated significant improvement in survival benefits at stage III NSCLC.4,5 Dr. Choi, Kwok-Keung Calvin, Specialist in Clinical Oncology, shared a case of a stage III NSCLC patient with an excellent prognosis after consolidation durvalumab therapy.
Stage III NSCLC presents as a heterogenous disease with several subclasses. Although stage IIIA with few nodes involved could be surgically removed, stage IIIA with multiple nodes, stage IIIB or IIIC, are considered unresectable or medically inoperable.
In this situation, unresectable refers to the impossibility of a complete resection even after the induction therapy, based on the evaluation within a multidisciplinary team (MDT).2 According to the current ESMO guidelines, concurrent CRT is the treatment of choice in patients diagnosed as unresectable in stage IIIA and IIIB. If concurrent CRT is not possible, sequential chemotherapy followed by definitive RT represents a valid and effective alternative.2 However, data on concurrent CRT did not show significant improvement in patients with stage III NSCLC. For example, 5-year OS remained at 26% for stage IIIB and 13% for stage IIIC over the past 10 years.6 The heterogenicity of the disease and individual patient variations could be reasons for this and multiple treatment approaches are necessary to combat the disease and deliver better outcomes.
Among the clinical trials which combined treatment modalities, the PACIFIC study is the pioneering study to combine durvalumab immunotherapy with concurrent CRT in patients with stage III NSCLC. Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-1).
The current case shared by Dr. Choi, was successfully treated with durvalumab after concurrent CRT. Dr. Choi further mentioned that, “During the last 5 years, the OS of stage III non-small-cell lung cancer was around 12%-15%, but the use of durvalumab after CRT has improved the OS significantly.”
The patient is a 60-year-old man who presented to hospital with dry cough in April 2018 at China. A computed tomography (CT) scan was conducted and found a space occupying lesion at the right upper lobe. The lesion was later identified as stage IIIC T3 N3M0 NSCLC. The cancer was tested for EGFR, ALK, and ROS1 mutations, but the results were negative. The patient then received induction chemotherapy with carboplatin, pemetrexed and bevacizumab for 3 cycles. Positron-emission tomography (PET) scans showed evidence of response to chemotherapy. The patient then went to the United States (US) and underwent concurrent CRT with proton radiation. Assessments including brain MRI showed no brain metastasis before the therapy. Concurrent CRT with dose 60 Gy in 30 fractions were performed, and chemotherapy was directed with weekly paclitaxel and carboplatin. The CRT was completed in August 2018 and PET scans showed no progression of the lesion. Adjuvant durvalumab was initiated back in Hong Kong in September 2018 and administered for every two weeks until October 2019. Figure 1A and 1B showed PET scans was done just after CRT on 20 September 2018 and on adjuvant immunotherapy on 15 August 2019. During the durvalumab treatment, a review was conducted every six months with CT and PET scans. No progression of the disease was observed. The patient’s tolerance and adverse events (AEs) were well monitored with thyroid-stimulating hormone (TSH) status, cortisol, blood glucose levels and liver and renal function tests and showed no significant adverse events. The most recent PET scan has shown complete response with no evidence of the disease (Figure 1). The patient is currently followed up with bi-annual CT screening in the US, together with every three months and annual PET-CT check-ups in Hong Kong.
PACIFIC was a randomized, double-blind, international phase 3 study comparing durvalumab, as consolidation therapy, with placebo in patients of stage III, locally advanced and unresectable NSCLC that had not progressed after platinum-based CRT.4 Durvalumab was administered from 1 to 42 days after the patients had received CRT. The case presented here showed exactly similar characteristics of patients and followed a similar treatment plan as in the PACIFIC trial. The median PFS from randomization in the PACIFIC trial was 17.2 months with durvalumab vs. 5.6 months with placebo (HR=0.51; 95% CI: 0.41-0.63; p<0.001).5 Moreover, the median duration of response was longer (73.5% vs. 52.2%) with durvalumab compared to placebo at 18 months.5 Additionally, the median time to death or distant metastasis was longer for durvalumab than for placebo (28.3 months vs. 16.2 months; p<0.001).5
Subgroup analyses and outcomes are important due to the heterogenicity of stage III NSCLC, particularly the PD-L1 levels. It was clearly shown that PFS has not been affected by PD-L1 levels.4 PACIFIC is the first and only study to have shown a significant OS improvement in stage III NSCLC patients. Most importantly, durvalumab also significantly prolonged OS, as compared with placebo (HR=0.69; 95% CI: 0.55-0.86) (Figure 2).7 The OS rates with durvalumab and placebo were 83.1% versus 74.6% for 12-month, 66.3% versus 55.3% for 24-month, and 57.0% versus 43.5% for 36-month, respectively (Figure 2). Moreover, in the updated subgroup analysis of OS, it was shown that results were consistent in regard to PD-L1 status with that reported at the primary OS analysis.7
In terms of the safety profile, durvalumab had comparable AEs as with previous studies. Nevertheless, patient reported outcomes suggested that the patients’ symptoms, functioning and global health status/quality of life were maintained regardless of PD-L1 expression, including patients with PD-L1 TC <1%.8 Dr. Choi also agreed with the findings and mentioned, “The patient tolerated durvalumab well and his quality of life was well maintained with continuous monitoring.” Thus, it is reassuring that the clinical benefit was attained with durvalumab without compromising any patient reported outcomes.9
The PACIFIC trial displayed survival advantages with durvalumab therapy after concurrent CRT in patients with stage III, unresectable NSCLC. It is also the first study to show survival improvement following CRT in stage III NSCLC outcomes. Durvalumab is the new standard of care with superior efficacy in OS, PFS and acceptable tolerability, putting “cure” as the treatment goal in stage III NSCLC.