Use of PD-L1 inhibitor consolidation therapy following concurrent chemoradiation in unresectable stage III NSCLC
Presentation and history
A 59-year-old male presented in November 2017 with hoarseness of voice. A CT scan performed in mainland China revealed a large mass in the left upper lobe of the lung. A subsequent PET-CT scan in December 2017 showed a 7.8 cm tumour adherent to the descending aorta with heterogeneous contrast enhancement and a very high standardized uptake value (SUV) of 29.0. The tissue plane between the descending aorta and the tumour was not distinct, suggesting invasion into the aorta, which rendered the patient inoperable. The left paratracheal lymph node was enlarged to 1.2 cm with an SUV of 4.1. No distant metastases were discovered.
Biopsy revealed poorly differentiated carcinoma, testing positive for TTF1 and p63 expression. SP142 test detected PD-L1 expression in 5 percent of tumour cells. On the basis of tumour size and involvement of an ipsilateral mediastinal lymph node, a clinical diagnosis of non-small-cell lung cancer (NSCLC) stage III, T4N2 was made.
Concurrent chemoradiation and subsequent immunotherapy
The patient received two initial cycles of chemotherapy with pemetrexed and carboplatin in mainland China in December 2017 and January 2018. He subsequently presented to our clinic for further treatment. MRI in January 2018 revealed no brain metastasis, while PET-CT in the same month showed a 6.7 cm tumour with a necrotic core and isometabolic lymph nodes, suggesting some response to chemotherapy. The tumour’s SUV estimated by a laboratory in Hong Kong was 5.1.
Further nonsurgical treatment was recommended in view of tumour adherence to major vessels. Concurrent chemoradiation with pemetrexed and carboplatin was commenced in late February 2018. Reassessment PET scan in April 2018, following two cycles of concurrent chemoradiation, showed further tumour shrinkage to 6.3 cm and a SUV of 5.0.
The patient commenced consolidation treatment with durvalumab (10 mg/kg every 2 weeks) in early May 2018, 39 days after receiving the last dose of chemoradiation, and continued durvalumab for 26 cycles until April 2019. PET-CT in November 2018, after 12 cycles of durvalumab, showed a tumour size of 5.8 cm, with SUV of 2.4. In May 2019, following 26 cycles of durvalumab, the tumour shrank to 4.0 cm and became isometabolic. According to the response evaluation criteria in solid tumours (RECIST) 1.1 criteria, partial response was achieved by durvalumab, while the latest PET scan carried out in December 2019, 8 months after the last administered dose of durvalumab, detected no active disease and revealed the primary residual tumour mass to be isometabolic, with a size of 4.1 cm.
Durvalumab treatment was very well tolerated by the patient, with the exception of a short period of hyperthyroidism, which manifested in May 2018 after two cycles of durvalumab and was successfully managed with carbimazole, until the patient’s T4 levels normalized in October 2018. The patient also experienced an increase in LDL-cholesterol level, which was managed with rosuvastatin that the patient still currently receives. No clinical or imaging evidence of pneumonitis was observed during or after treatment.
Stage III NSCLC represents a heterogeneous group of tumours, whose management is among some of the most controversial and complicated topics in clinical oncology. Appropriate staging is the first hurdle to selecting optimal treatment. While modern imaging methods may help identify distant metastases, additional pathological proof (through endobronchial ultrasound biopsy) may be required in cases of suspected lymph node involvement, as it is not uncommon for patients in South-East Asia to have metabolically active lymph nodes due to latent infection such as tuberculosis. Other complexities in stage III NSCLC management are related to patients’ genetic make-up, tumour resectability and the use of multiple treatment modalities, all of which require expertise of a multidisciplinary team involving oncologists, surgeons and radiologists.
Since our patient’s bulky T4 tumour with likely major vessel invasion was deemed unresectable, he was offered concurrent chemoradiation, which offers longer overall survival (OS) in locally advanced NSCLC vs sequential treatment and has been the standard of care for physically fit patients with unresectable stage III NSCLC over the past decade.1
The US National Comprehensive Cancer Network (NCCN) guidelines also recommend consolidation therapy with the PD-L1 inhibitor durvalumab in patients who retain a good performance status with no disease progression after concurrent chemoradiation.2
Our patient was commenced on durvalumab maintenance on the basis of the significantly prolonged OS vs placebo reported in the phase III PACIFIC study in patients with unresectable stage III NSCLC who did not have disease progression after concurrent chemoradiation (27 percent Asians). After a median follow-up of 25.2 months, the stratified hazard ratio (HR) for death was 0.68 (99.73 percent confidence interval [CI], 0.47 to 0.997; p=0.0025), while the 24-month OS rate was 66.3 percent in the durvalumab group vs 55.6 percent in the placebo group (two-sided p=0.005).3
Updated PACIFIC study results after a median follow-up of 33.3 months demonstrated that durvalumab consolidation treatment continued to significantly prolong OS vs placebo (median, not reached [NR] vs 29.1 months; stratified HR, 0.69; 95 percent CI, 0.55 to 0.86). The 36-month OS rate with durvalumab was 66.3 percent vs 43.5 with placebo.4
The PACIFIC study also demonstrated durvalumab’s good tolerability, as evidenced by the comparable incidence of grade 3/4 toxicities between the placebo and durvalumab groups (26.1 percent vs 30.5 percent).3 However, it should be noted that the study focused on fit patients, such as ours, with a WHO performance status score of 0–1, and its results may not be applicable to weaker patients.
Preclinical studies have demonstrated upregulation of PD-L1 expression on the cell surface of irradiated tumours, which leads to enhanced tumour immunogenicity.5,6 In view of the synergistic antitumour activity of the two modalities, the use of immunotherapy following radiotherapy appears to be a sensible treatment strategy. However, given the observed increase in PD-L1 expression following radiation treatment in animal models, the results of PD-L1 testing prior to radiotherapy cannot be viewed as a reliable predictor of immunotherapy’s efficacy. Notably, improvement in OS and progression-free survival (PFS) with durvalumab was shown across all prespecified subgroups of the PACIFIC trial, irrespective of PD-L1 expression status.3 Therefore, durvalumab use is not restricted to PDL-1–positive tumours in certain guidelines such as the NCCN.
While EGFR mutations are especially prevalent among Asian NSCLC patients (47.9 percent vs 19.2 percent of Western patients) and multiple effective EGFR-targeted tyrosine kinase inhibitors exist, no data is available regarding their use in unresectable stage III NSCLC.7 Therefore, we did not test for EGFR mutation in our patient, as its result would not have a bearing on his treatment.
In the absence of maintenance treatment following chemoradiation, unresectable stage III NSCLC patients are very likely to relapse within a short period, as evidenced by the PFS of the placebo group (5.6 months vs 17.2 months for durvalumab; HR, 0.51; 95 percent CI, 0.41 to 0.63) of the PACIFIC trial.3 Durvalumab consolidation therapy can prolong their survival following concurrent chemoradiation.