PD-L1 inhibitor use in patients with stage III NSCLC
Presentation and investigations
A 65-year-old male patient was referred to our care by his thoracic surgeon, having undergone left pneumonectomy that included lymph node resection. Pneumonectomy was undertaken as preoperative PET-CT failed to reveal lymph node involvement, which only became apparent during mediastinal lymph node dissection. The patient was diagnosed with poorly differentiated T2N2 stage III squamous cell carcinoma.
Treatment and response
Due to the involvement of multiple N2 station nodes, including the aortopulmonary window, subcarinal and left peribronchial nodes, the patient was commenced on 6 weeks of concurrent chemoradiation. Between September and November 2018, he received weekly carboplatin (2 mg/mL/min) and paclitaxel (40 mg/m2). Treatment was generally well tolerated with no significant radiation pneumonitis recorded.
The first cycle of durvalumab was commenced on 12 November 2018, 9 days after the patient’s last fraction of radiation. As of July 2019, the patient had received 19 cycles of durvalumab (10 mg/kg intravenously, once every 2 weeks) and will continue with the recommended 26-cycle course.
The patient was followed up regularly, with assessments including low-dose CT of the thorax (to ensure there was no recurrence in the mediastinal nodes and lungs) and MRI of the brain. (Figure 1) On his last follow-up in May 2019, the patient’s disease was stable with no evidence of brain metastases. He has not suffered any immune-related adverse effects (IRAEs), such as skin rash, allergic cholitis, pneumonitis or hypersensitivity of the internal organs, as a result of durvalumab treatment.
Presentation and investigations
A 63-year-old male patient presented with cough and haemoptysis in April 2018. He initially underwent CT scan and next-generation sequencing (NGS) in mainland China before presenting to us. We subsequently carried out an additional PET-CT that revealed hyperactive, hypermetabolic subcarinal nodes and very active N2 station nodes; a brain MRI showed no evidence of distant metastases at the time. The patient was diagnosed with right lower lobe T2N2M0 stage IIIA adenocarcinoma. NGS reported ALK mutations and a high tumour mutational burden with over 23 mutations per megabase.
Treatment and response
Following diagnosis, the patient was advised to undergo chemoradiation therapy, but he chose to return to mainland China where he underwent video-assisted thoracoscopic surgery (VATS) with right lower lobectomy and mediastinal nodal dissection in August 2018. Pathology results confirmed the diagnosis of adenocarcinoma with visceral pleural invasion, evident in his preoperative PET-CT.
At this point, the patient returned to Hong Kong to seek postoperative adjuvant treatment. In August 2018, he was treated with a combination of carboplatin and pemetrexed for a total four cycles. This was followed by 30 fractions of radiotherapy during November and December 2018. A repeat CT scan in December 2018 showed no evidence of recurrence.
In January 2019, the patient was initiated on maintenance treatment with durvalumab 10 mg/kg as we believed that there was still a 10–15 percent chance of cure and that he could thus benefit from durvalumab in the postoperative, postchemoradiation setting. The patient was followed up regularly, with assessments including low-dose CT of the thorax to ensure there was no tumour recurrence. (Figure 2) As of July 2019, he had received 13 cycles of durvalumab, with no evidence of recurrence. The patient is tolerating his durvalumab treatment well, without any evidence of IRAEs to date.
Although the two cases presented do not strictly match the inclusion criteria of the PACIFIC trial,1 both demonstrate the successful use of durvalumab in a real-world setting, where stage III NSCLC patients form a heterogeneous population and are managed through various treatment modalities. In each of the presented cases, the purpose of preventing or postponing disease recurrence following locoregional chemoradiation has been attained to date. Both patients have responded well to treatment, with one of them showing disease stabilization and the other having no evidence of recurrence. Neither patient has experienced IRAEs during the course of treatment.
In the PACIFIC study, patients with locally advanced, unresectable non-small-cell lung cancer (NSCLC) were randomly assigned within 1 to 42 days after chemoradiotherapy to receive intravenous durvalumab at a dose of 10 mg/kg or matching placebo every 2 weeks as consolidation therapy for up to 12 months. At 25.2-month follow-up, progression-free survival (PFS) was 11 months longer among patients who received durvalumab compared with those who received placebo (median, 17.2 months vs 5.6 months; stratified hazard ratio [HR] for disease progression or death, 0.51; 95 percent confidence interval [CI], 0.41 to 0.63; p<0.001).1
Updated PACIFIC trial results, after a median follow-up of 33.3 months (range, 0.2 to 51.3 months), demonstrated that durvalumab significantly prolonged overall survival (OS) compared with placebo (median, not reached [NR], [95 percent CI, 38.4 to NR] vs 29.1 months [95 percent CI, 22.1 to 35.1]; stratified HR for death, 0.69; 95 percent CI, 0.55 to 0.86). At 36 months, 57 percent of patients receiving durvalumab vs 43.5 percent of patients receiving placebo remained alive.2
The difference in overall survival (OS) and PFS in favour of durvalumab was shown across all prespecified subgroups of the PACIFIC trial. Notably, the longer OS and PFS were accomplished in a biomarker-independent population; patients with a <25 percent level of PD-L1 expression accounted for a larger proportion of PACIFIC participants than patients with ≥25 percent PD-L1–positive tumour cells (41 percent vs 22.3 percent; 36.7 percent of patients had unknown PD-L1 status).3 This means that patients do not need to undergo PD-L1 testing prior to the start of durvalumab therapy, which saves time.
Updated results for secondary endpoints, including the time to death or distant metastasis, the incidence of new lesions, and the objective response rate, remained consistent with those that were previously reported and continued to show the substantial anticancer activity of durvalumab in patients after induction therapy.2 Durvalumab’s favourable effect on preventing metastasis allows patients to remain well for longer and corresponds with the survival benefit demonstrated in the PACIFIC trial.
In addition, durvalumab therapy resulted in an 11-month longer time to second progression or death than placebo (median, 28.3 months; [95 percent CI, 25.1 to 34.7], vs 17.1 months; [95 percent CI, 14.5 to 20.7]), as well as longer times to the first subsequent therapy or death and to the second subsequent therapy or death vs placebo.1 These results are indicative of the long-term benefit of durvalumab treatment.
In the PACIFIC study, the incidence of grade 3 or 4 adverse events (AEs) was 30.5 percent in patients who received durvalumab vs 26.1 percent in patients receiving placebo. Discontinuation of the trial regimen because of AEs occurred in 15.4 percent of patients in the durvalumab group vs 9.8 percent of patients in the placebo group. The most frequent AEs leading to the discontinuation of the trial regimen were pneumonitis (4.8 percent of patients in the durvalumab group vs 2.6 percent of those in the placebo group), radiation pneumonitis (1.3 percent vs 1.3 percent), and pneumonia (1.1 percent vs 1.3 percent).1 While neither patient described above had suffered any IRAEs, it should be noted that they have yet to complete their 12-month treatment with durvalumab, which is within the at-risk period for IRAEs, especially pneumonitis, for PD-1/PD-L1 therapies.4,5
The ultimate aim of treatment of stage III NSCLC is cure. Patients should not be denied the opportunity of cure, even when only the smallest chance exists. In view of its proven clinical benefits and good safety profile, durvalumab represents a viable treatment option for patients with potentially curable stage III NSCLC.