"Tsunami study: five years later, the fallout is still there

Preface: The PACIFIC study ended the embarrassing situation of no maintenance therapy after concurrent radiotherapy in patients with locally advanced NSCLC, bringing new treatment options to this group of patients. The study's PFS and OS results were published in the New England Journal of Medicine, and it is one of the few studies in lung cancer in which both PFS and OS analyses were published in this top journal. The 5-year follow-up data from the study was recently published in JCO.

Research Overview

"Tsunami study: five years later, the fallout is still there

Research Background

The PACIFIC study explored the efficacy and safety of Durvalumab given as maintenance therapy after standard concurrent radiotherapy if it did not progress in patients with locally advanced inoperable non-small cell lung cancer. The study obtained double-positive results for PFS and OS and established Durvalumab as a treatment in multiple countries, ending the situation of only passive observation after synchronous radiotherapy. The purpose of this study is to provide 5-year follow-up data and results from the PACIFIC study.

Research Methodology

This is a phase III, placebo-controlled study enrolling inoperable stage III non-small cell lung cancer patients with a PS score of 0-1 who received at least two cycles of chemotherapy followed by concurrent radiotherapy at a total radiotherapy dose of 60-66 Gy. The study was stratified based on age (65 years), sex, and smoking status. Patients meeting the enrollment criteria were randomized in a 2:1 ratio to the Durvalumab or placebo group. the upper limit of Durvalumab treatment was 12 months. The primary study endpoints were PFS and OS as assessed by an independent review board, and secondary study endpoints included ORR, DOR, and time to appearance of distant metastases.

Study results

A total of 709 patients were randomized, and 473 and 236 patients were enrolled in the Durvalumab and placebo groups, respectively, with balanced and comparable baseline characteristics between the two groups. By January 2021, 55.5% and 65.4% of patients in the two groups, respectively, had a mortality event. The median follow-up time was 34.2 months for the whole group and 61.6 months for patients with tail amputation, with 49% and 34.7% of patients in the two groups completing 12 months of treatment, respectively. After disease progression, 48.5% and 58.6% of patients received follow-up treatment, most commonly chemotherapy, in 33% and 35.9% of both groups, respectively. median OS at 5-year update was 47.5 months and 29.1 months, HR=0.72 (95% CI, 0.59-0.89), with 5-year OS rates of 42.9% and 33.4% in both groups, respectively. Median PFS was 16.9 months and 5.6 months in both groups, HR=0.55. 5-year PFS rates were 33.1% and 19.0%, respectively.

"Tsunami study: five years later, the fallout is still there

Benefits in PFS and OS were observed in different subgroup analyses, but no benefit in OS was observed in patients with PD-L1 <1%.

"Tsunami study: five years later, the fallout is still there

HR=0.59 for the two groups to the time of appearance of distant metastases. the rate of appearance of new lesions in the two groups was 24.2% and 33.3%, respectively, and the rate of appearance of brain metastases was 6.5% and 11.8%, respectively. ORR was 29.8% and 18.3% in the two groups, respectively. The median DOR was not reached and 18.4 months, respectively. 81.1%, 58.7%, and 51.1% of patients in the Durvalumab group who developed an objective response had a response persistence rate at 1, 3, and 5 years, respectively; 60.5%, 34.5%, and 0% of patients in the placebo group had a response persistence rate at 1, 3, and 5 years, respectively. Univariate analysis found that age <65 years, objective response during induction, PS score 0, cisplatin use, and Asian population were associated with better prognosis; multifactorial analysis found that age <65 years, non-squamous cancer, PS score 0, and Asian patients were still associated with better OS.

"Tsunami study: five years later, the fallout is still there

Research findings

This updated analysis confirms that treatment with Durvalumab given to patients who have not progressed after concurrent radiotherapy provides a sustained benefit in PFS and OS. It is the standard of care treatment option for this group of patients.

Unanswered questions from the PACIFIC study

The PACIFIC study has undeniably established Durvalumab as an important treatment in patients with locally advanced, inoperable resection. In addition to topping the New England Journal of Medicine for both PFS and OS results, the study's annual data updates always attract industry attention and are published in JTO, the leading journal for thoracic oncology.Despite the importance of the PACIFIC study, however, three aspects of the study remain open to question.

First, mutation-positive patients were included. At the same time as the 4-year OS data were published, the PACIFIC study also published a subgroup analysis based on driver mutations. Patients carrying driver mutations had a median HR of 0.94 for PFS and 0.97 for OS in both groups, while the JTO journal had also published two retrospective studies exploring the benefit of maintenance treatment with Durvalumab in patients positive for driver mutations. In the first study, patients carrying/not carrying EGFR or HER2 mutations received maintenance treatment with Durvalumab with a median PFS of 7.5 months and not achieved, respectively.P=0.04, the PFS at 7.5 months after maintenance treatment with Durvalumab in patients in the mutation group was almost similar to the data from the control group of patients in the PACIFIC study. In contrast, the findings of another study were similar, with data from observation alone (group A), maintenance treatment with Durvalumab (group B) and maintenance treatment with EGFR-TKI (group C) after simultaneous radiotherapy, with median PFS of 6.9 months, 10.3 months and 26.1 months in the three groups, respectively, where the difference was not statistically significant in group A compared with group B (P= 0.993).

"Tsunami study: five years later, the fallout is still there

In mutation-positive patients, some studies have begun to explore the efficacy and safety of concurrent targeted radiotherapy and have obtained excellent results. A small randomized controlled study done by Chinese scholars found that the median PFS was 24.5 months and 9.0 months (HR=0.10) for patients treated with synchronous radiotherapy and synchronous targeted radiotherapy, respectively, with immature OS, while a small sample single-arm study conducted by Japanese scholars published in JTO journal found that for inoperable locally advanced NSCLC patients carrying EGFR-sensitive mutations Administration of synchronous target radiotherapy (gefitinib combined with standard-dose radiotherapy) significantly improved patient prognosis compared with historical data, with a median PFS of 18.6 months, a 2-year PFS rate of 29.6%, and a median OS of 61.1 months in 27 patients, already exceeding the median OS data of about 48 months in the PACIFIC study.

Second, patients with PD-L1 <1%. july 2020Annals of OncologyA subgroup analysis of the PACIFIC study based on PD-L1 expression levels was published online in the journal. If 1% was used as the cut-off value, for patients with PD-L1 ≥1%, median PFS was 17.8 and 5.6 months (HR=0.46, 0.33-0.64) and median OS was not reached and 29.6 months (HR=0.59, 0.41-0.83) for the two groups, respectively; whereas for patients with PD- L1 <1% patients, the median PFS was 10.7 and 5.6 months (HR=0.73, 0.48-1.11) for both groups, and the median OS was 33.1 and 45.6 months (HR=1.14, 0.71-1.84) for both groups, respectively. In contrast, at the time of this data update, there was indeed no OS benefit observed in patients with PD-L1 <1%. This is why in Europe, patients with PD-L1 <1% did not receive relevant indications.

Third, the combined modality of radiotherapy and chemotherapy. Although simultaneous radiotherapy and chemotherapy is the standard treatment modality for this group of patients, only 20-25% of patients in China can complete this treatment modality considering the safety, and sequential radiotherapy remains the treatment choice for most patients. Recently, a study published inLancet OncologyThe Journal's GEMSTONE-301 study, on the other hand, explored the efficacy and safety of sugilizumab, a PD-L1 inhibitor, given for 2 years to patients who had not progressed after the administration of concurrent/sequential radiotherapy. At the time of data publication, the median PFS was 9.0 months and 5.8 months for the two groups, respectively, with HR=0.64; for patients who received synchronous radiotherapy, the median PFS was 10.51 months and 6.37 months for the two groups, respectively, with HR=0.66, while for patients who received sequential radiotherapy, the median PFS was 8.0 months and 4.07 months for the two groups, respectively, with HR=0.59. The median for the two groups OS was immature, and the incidence of treatment-related adverse events of 3rd degree and higher was 9% and 6%, respectively. This study then provides a high-level evidence-based rationale for patients to receive immune maintenance therapy after sequential radiotherapy.

"Tsunami study: five years later, the fallout is still there

There may be questions from readers as to why there is a near 1-fold difference in PFS between the two studies. The reasons are multiple, and the difference in baseline characteristics is an important reason, including stage (29%, 57% and 13% of stage IIIa-IIIc in the GEMSTONE-301 study, respectively; in the PACIFIC study, no stage IIIc patients were enrolled, and 52.9% and 44.5% of stage IIIa and IIIb patients were enrolled, respectively), tissue There were significant differences between the two groups in terms of pathological type (the most common type in the GEMSTONE-301 study was squamous carcinoma at 69%, whereas the most common type in the PACIFIC study was non-squamous carcinoma at 52.9%), and driver gene mutations (the PACIFIC study allowed the enrollment of mutated patients, but the GEMSTONE-301 study did not). Therefore, it is not surprising that there were differences in median PFS.