Neoadjuvant Pembrolizumab for Early Stage Non-Small Cell Lung Cancer
新輔助Pembrolizumab治療早期非小細胞肺癌
Introduction
介紹
Neoadjuvant immune checkpoint inhibitor treatment is a promising approach for resectable cancer. The optimal treatment regimen has yet to be determined.
This study was initially reported at the ESMO annual meeting 2018 and at the ASCO 2019 annual meeting. We currently report the final analysis for safety, the primary endpoint of the study, and updated efficacy results.
新輔助免疫檢查點抑製劑治療是一種很有前景的可切除腫瘤的方法。最佳的治療方案尚未確定。這項研究最初在2018年ESMO年會和2019年ASCO年會上進行了報道。我們目前報告了安全性的最終分析、研究的主要終點和最新的療效結果。
Methods
研究方法
We have conducted a phase I, investigator-initiated single-center study, to examine the safety of neoadjuvant pembrolizumab for stage I-II (TNM v7) resectable NSCLC, to identify the recommended phase II dose/schedule (RP2D/S) and to evaluate efficacy by remaining viable cells (10% or less defined as a major pathologic response, MPR). The study cohorts differed in number of pembrolizumab doses, and in treatment initiation-to-surgery intervals. Exploratory analyses were done to evaluate factors possibly correlated with MPR.
我們已經進行了第一階段,研究者發起的單中心研究中,檢查安全的新輔助pembrolizumab階段I II (TNM v7)可切除的非小細胞肺癌,確定推薦的二期劑量/時間表(RP2D / S)和評估療效剩餘可行的細胞(10%或更少定義為一個主要的病理反應,MPR)。研究隊列在派姆單抗劑量數量和治療開始至手術間隔上有所不同。探索性分析可能與MPR相關的因素。
Results
結果
26 patients initiated treatment on the study. Median age: 69 (range 51-79) years, 54% men, smoking status: 62%/31%/8% current/past/never. ECOG PS: 1/0 in 85%/15%. Histology: adenocarcinoma/squamous/adeno-squamous/NSCLC in 50%/42%/4%/4%. No DLT and no grade 5 TRAE occurred. Two patients (8%, 95% C.I 0-18%) had grade 3-4 TRAE; one patient had both grade 3 myositis and myocarditis (causing surgery deferral) and one patient had both grade 3 encephalitis and hepatitis (following surgery, 124 and 171 days respectively from pembrolizumab initiation). Median change in tumor diameter radiologically was -5% (range, -43% to 70%). By RECIST, one patient (4%; 95% C.I. 0-11%) had PR, 21 patients (81%; 95% C.I. 66-96%) had SD, two patients (8%; 95% C.I. 0-18%) had PD and two patients were non-evaluable. One patient refused surgery after treatment and one patient had a non-treatment-related myocardial infarct leading to surgery deferral. Pathologically, 7 patients (27%, 95% C.I 10-44%) achieved a MPR, 3 (12%, 95% C.I 1-24%) achieved pCR. Patients with MPR had longer treatment-surgery interval (Table). At a median follow up of 23 months (95% CI 13-32), 2 patients of the 26 treated patients (8%, 95% C.I 0-18) died, one of them with no evidence of disease. One of the 23 operated patients (4%, 95% C.I. 0-13%) had disease recurrence.
26例患者在研究中開始治療。中位年齡:69歲(範圍51-79)，54%男性，吸煙狀況:62%/31%/8%目前/過去/從未吸煙。ECOG PS: 1/0在85%/15%。組織學:腺癌/鱗癌/腺鱗癌/非小細胞肺癌占50%/42%/4%/4%。未發生DLT和5級TRAE。2例患者(8%，95% C.I 0-18%)有3-4級TRAE;1例患者同時患有3級肌炎和心肌炎(導致手術延遲)，1例患者同時患有3級腦炎和肝炎(術後，派姆單抗啟動124天和171天)。影像學上腫瘤直徑的中位變化為-5%(範圍為-43%至70%)。RECIST有1例患者(4%;95% C.I. 0-11%)有PR, 21例(81%;95% C.I. 66-96%)有SD, 2例(8%;95% C.I. 0-18%)有帕金森病，2例患者無法評估。1例患者在治療後拒絕手術，1例患者出現與治療無關的心肌梗死，導致手術延期。病理上，7例(27%，95% C.I 10-44%)達到MPR, 3例(12%，95% C.I 1-24%)達到pCR。MPR患者的治療-手術間隔較長(表)。中位隨訪23個月(95% CI 13-32)， 26例治療患者中有2例(8%，95% CI 0-18)死亡，其中1例無疾病跡象。23例手術患者中有1例(4%，95% C.I. 0-13%)有複發。
Parameter |
MPR achieved |
No MPR |
P value |
N |
7 |
16 |
|
Age - median (min-max) years |
71 (66-73) |
64 (51-79) |
0.138 |
Male - n (%) |
6 (86%) |
6 (38%) |
0.069 |
Smoking status – n (%) |
1.000 |
||
Yes |
5 (71) |
10 (63) |
|
Past |
2 (29) |
5 (31) |
|
Never |
0 (0) |
1 (6) |
|
Pathology – n (%) |
1.000 |
||
Adenocarcinoma |
4 (57) |
7 (44) |
|
Squamous |
3 (43) |
7 (44) |
|
Adeno-Squamous |
0 (0) |
1 (6) |
|
NSCLC |
0 (0) |
1 (6) |
|
Tumor size - Avg (min-max) mm |
32 (24-48) |
33 (11-74) |
0.822 |
T stage - n (%) |
|||
T1b |
3 (18) |
||
T1c |
4 (57) |
6 (35) |
|
T2a |
2 (29) |
3 (18) |
|
T2b |
1 (14) |
2 (12) |
|
T3 |
1 (6) |
||
T4 |
1 (6) |
||
N stage - n (%) |
0.416 |
||
N 0 |
7 (100) |
14 (88) |
|
N 1 |
0 (0) |
2 (12) |
|
PDL1 - median (min-max) % |
1 (0-65) |
2 (0-85) |
0.632 |
Treatment initiation-Surgery interval - median (min-max) days |
43 (38-52) |
36 (23-62) |
0.043 |
Comparison of patients that underwent surgery (n=23) with and without MPR |
|||
Conclusion
結論
Neoadjuvant pembrolizumab for early NSCLC achieved a 27% rate of MPR, a 12% rate of pCR, with 8% rate of grade 3-4 TRAE. Two doses of neoadjuvant pembrolizumab at a three week interval, followed by surgery two weeks later, is the RP2D/S. Longer interval from treatment to surgery was associated with higher rate of MPR. Correlative studies are ongoing.
早期NSCLC的新輔助派姆單抗達到27%的MPR率，12%的pCR率，8%的3-4級TRAE率。RP2D/S為每三周間隔兩劑新輔助派姆單抗，兩周後進行手術。從治療到手術的較長時間間隔與較高的MPR率相關。相關研究正在進行中。
