Non–Small-Cell Lung Cancer
未做化療 腫瘤有PDL1表象的病人反應率是50%(Opdivo), 26%(Keytruda)
做過化療反應率是16%- 23%
腫瘤有PDL1表象的病人反應率是23% - 46%
腫瘤沒有PDL1表象的病人反應率是3% - 15%
做過化療後 PDL1表象不再重要 有PDL1表象的病人反應率是15% 沒有PDL1表象的病人反應率是14%
吸煙者反應率是25% 非吸煙者反應率是8% - 16%
The PD-1/PD-L1 pathway appears to be a critical therapeutic target for advanced NSCLC. Multiple PD-1 and PD-L1 antibodies have demonstrated antitumor activities in both pre- and postsystemic therapy settings. The activity appears to be more pronounced in earlier disease settings. As shown in Table 5, in chemotherapy-naive, PD-L–positive patients, nivolumab[31] and pembrolizumab[32] demonstrated ORRs of 50% (95% CI, NR) and 26% (95% CI, 14–42), respectively. In pretreated patients, nivolumab,[33] pembrolizumab,[34] MPDL3280A, [35] and MEDI4736[36] have demonstrated ORRs ranging from 16% to 23%.
Brahmer et al presented survival data of a phase Ib trial of nivolumab that included 129 heavily pretreated patients with advanced NSCLC, more than half of whom received > 3 prior therapies.[33] At a median follow-up of 27 months across all dose levels, 1- and 2-year OS rates were 42% (95% CI, 34–51) and 24% (95% CI, 16–32), respectively, and median OS was 9.9 months (95% CI, 9.8–12.4). Patients given the 3-mg/kg dose appeared to have superior survival data, with 1- and 2-year OS rates of 56% (95% CI, 38–71) and 45% (95% CI, 27–61), respectively, and a median OS of 14.9 months (95% CI, 7.3–NR). Unlike cytotoxic agents—and as seen in other settings, such as in mRCC[25]—nivolumab did not show a clear dose-response relationship in advanced NSCLC. The survival data are certainly encouraging in a disease where the median OS has been no more than 7 to 8 months.
PD-L1 expression on NSCLC tumor cells or tumor-infiltrating immune cells was associated with higher response rates. Although not statistically powered to show this, some degree of correlation has been observed with most of the agents, including pembrolizumab, MPDL3280A, and MEDI-4736. As noted in Table 5, across all these agents, except nivolumab in pretreated patients, PD-L1 expression was associated with higher response rates. ORRs were 23% to 46% vs 3% to 15% in PD-L1–positive vs PD-L1–negative groups, respectively.
As also noted, while PD-L1 expression was highly predictive of response to nivolumab in treatment-naive patients (50% in PD-L1–positive patients vs 0% in PD-L1–negative patients),[31] this was not the case for pretreated patients (15% in PD-L1–positive vs 14% in PD-L1–negative), using 5% as a PD-L1 expression cutoff.[33] This difference, despite the use of the same assay and the same drug, raises several questions, including questions of assay sensitivity, of archival tissue vs “fresh” pretreatment biopsy, and of whether the complexity of immune-mediated cytolysis is underestimated. Several ongoing phase III trials of nivolumab in advanced NSCLC require mandatory tissue samples and will explore the role of PD-L1 as a predictive biomarker for nivolumab, with its prespecified evaluation correlated to OS (see Table 7).
Another important potential predictive biomarker is smoking status. Both MPDL3280A[35] and pembrolizumab[34] have demonstrated higher response rates among current or former smokers than among never-smokers. Among current/former smokers, ORRs by RECIST 1.1 were 25% (95% CI, NR) and 26% (95% CI, 19–35) with MPDL3280A and pembrolizumab, respectively. Among never-smokers, ORRs were 16% (95% CI, NR) and 8% (95% CI, 3–18) with MPDL3280A and pembrolizumab, respectively. It has been hypothesized that because lung cancers in smokers are associated with more genetic mutations, they generate new tumor-associated or tumor-specific antigens, which are rendered more susceptible to recognition by immune cells. Thus, when an immune checkpoint such as PD-L1 is blocked, these patients’ immune cells may be more likely to respond and induce immune-mediated tumor cell killing.
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