We assessed overall survival in the subgroup of 82 patients with advanced, ALK-positive NSCLC who had enrolled on the multicentre phase 1 clinical trial of crizotinib.17
These patients were mainly young (median age 51 years [range 25–78]), never smokers with adenocarcinoma histology, as previously reported.17
Among the 82 patients, 50 (61%) were enrolled at US study sites, 26 (32%) at the Korean site, and the remaining six (7%) in Australia. Since the protocol placed no restriction on the number of previous therapies, this number varied widely among patients, ranging from zero to seven previous lines (median two) of therapy for metastatic disease. 73 (89%) of the 82 patients had received at least one previous therapy for metastatic disease. As shown in , median overall survival from the date of first crizotinib dose has not been reached (95% CI 17 months to not reached), 1-year overall survival was 74% (95% CI 63–82), and 2-year overall survival was 54% (40–66). Overall survival did not differ based on age (≤50 vs
>50 years, p=0·692), sex (p=0·975), smoking history (never vs
any smoking, p=0·857), or ethnic origin (Asian vs
non-Asian, p=0·857; webappendix
p 2). Median follow-up for the 82 crizotinib-treated patients was 18 months (IQR 16–22).
Overall survival for ALK-positive, crizotinib-treated patients
Our control group of 36 ALK-positive patients who had not received crizotinib () had been screened at four study sites (three in the USA, one in Australia) over the same time period as crizotinib-treated patients. Since no ALK-positive controls were identified at the Korean study site by the cutoff date of Feb 10, 2010, and since Asians might have different crizotinib pharmacokinetics than white people,25
we compared control, crizotinib-naive patients with the non-Korean cohort of crizotinib-treated patients (n=56). As shown in , both demographic and clinicopathological characteristics were well balanced between the 36 control and 56 crizotinib-treated, ALK-positive patients. The groups were also well balanced in terms of presence of brain metastases at any time during the disease course. Whereas the number of previous therapies for metastatic disease ranged from zero to seven for crizotinib-treated patients, the number of therapies for ALK-positive control patients ranged from one to four. However, the median number of therapies was two for both groups (). Additionally, control and crizotinib-treated patients had received similar types of standard therapies for advanced NSCLC, including platinum-based combination chemotherapy, pemetrexed or pemetrexed-containing regimens, and erlotinib or erlotinib-based regimens ().
Demographic and clinicopathological characteristics of ALK-positive patients
Treatment histories of ALK-positive patients
Overall survival in the 56 crizotinib-treated patients, calculated from the date of first crizotinib dose, was similar to that for the entire cohort of 82 patients: median overall survival has not been reached (95% CI 17 months to not reached); 1-year overall survival was 71% (95% CI 58–81), and 2-year overall survival was 57% (40–71). Median overall survival for the 36 crizotinib-naive, ALK-positive control patients, measured from the time of metastatic diagnosis, was 20 months (95% CI 13–26); 1-year overall survival was 72% (95% CI 54–84), and 2-year overall survival was 36% (19–54). However, the comparison of crizotinib-treated and crizotinib-naive patients is complicated by the fact that patients received crizotinib at different lines, from first-line through eighth-line (). For both groups, assessing overall survival from the time of metastatic diagnosis is complicated by the fact that 20 (36%) of 56 crizotinib-treated patients received between three and seven previous lines of therapy. Thus, this approach could overestimate the survival benefit associated with crizotinib. We therefore examined survival outcomes among less heavily pretreated patients. Since only six (11%) of the 56 patients within the non-Korean cohort received crizotinib first-line, we could not compare survival outcomes in the first-line setting. Instead, we focused on the subset of patients who received crizotinib as second-line or third-line therapy and the subset of ALK-positive controls who received any second-line therapy. The clinicopathological features of these two subsets were comparable (webappendix
p 3). Among 30 non-Korean patients given crizotinib in the second-line or third-line setting, median overall survival from crizotinib dosing has not been reached (95% CI 14 months to not reached); by contrast, median overall survival of 23 crizotinib-naive controls treated with any second-line therapy was 6 months (4–17; ). 1-year overall survival was 70% (95% CI 50–83) for the crizotinib-treated subset versus 44% (23–64) for the crizotinib-naive subset; 2-year overall survival was 55% (33–72) versus 12% (2–30), respectively (HR 0·36, 95% CI 0·17–0·75; p=0·004). Similar results were obtained even when patients at the Korean study site treated with second-line or third-line crizotinib were included in this subset analysis (webappendix
p 1). These results suggest that crizotinib might substantially improve survival outcomes in patients with advanced ALK-positive NSCLC.
Overall survival for crizotinib-treated versus crizotinib-naive, ALK-positive patients
To address whether the ALK-positive, crizotinib-naive controls were a valid comparator group for this survival analysis, we examined the screening and selection of control patients. Among the 36 controls, 12 (33%) were identified retrospectively and were not screened for the purposes of trial enrolment. These retrospective controls should accurately represent the natural history of ALK-positive NSCLC. The remaining 24 controls (67%) were identified prospectively with the intention of enrolling on the phase 1 trial. Ten (42%) of the 24 prospective controls remain trial eligible and could receive crizotinib on disease progression. The remaining 14 (58%) of the prospective controls did not receive crizotinib for various reasons, including 11 with unanticipated clinical deterioration (often while waiting for evidence of disease progression) or protocol eligibility issues, or both, and three who were lost to follow-up and never referred to a trial site. To assess whether the prospective controls might represent a subset of patients with a particularly poor prognosis, we compared overall survival for prospective and retrospective controls from the time of metastatic diagnosis. Compared with retrospective controls, prospective controls did not show a significant difference in overall survival (median 26 months [95% CI 13–48] vs
18 months [6–22], p=0·195; webappendix
p 4). The lack of a significant difference might be a reflection of the small sample size of each group. However, these findings do support the use of both retrospectively and prospectively identified patients within the ALK-positive control cohort, since they could represent similar prognostic groups.
To evaluate the survival outcomes of ALK-positive patients in the context of the general NSCLC population, we identified an ALK-negative control group of patients with advanced NSCLC. This ALK-negative group was identified at the same time as the ALK-positive group through large-scale screening efforts at one US study centre (MGH). All patients were screened for ALK
rearrangement and EGFR
mutation. Among the 320 ALK-negative patients, we identified 67 with known EGFR
sensitising mutations, referred to as EGFR-positive, and 253 without EGFR
mutations (). Patients with atypical EGFR
mutations such as exon 20 insertion were not included in this analysis. Patients who were both ALK-negative and EGFR-negative are referred to as wild-type. summarises the demographic and clinicopathological features of ALK-positive, EGFR-positive, and wild-type patients. The cohort of 92 ALK-positive patients includes the 56 non-Korean, crizotinib-treated patients plus the 36 ALK-positive controls. Consistent with published studies,4,12,13,15
ALK-positive patients were significantly younger than either EGFR-positive or wild-type patients (p<0·0001; ). Other significant differences between ALK-positive and wild-type patients included never or light smoking history (91% vs
38%, p<0·0001) and adenocarcinoma histology (96% vs
88%, p=0·041). By contrast, ALK-positive and EGFR-positive patients were very similar with respect to smoking history and histological subtype (). For all three groups, the proportion of patients with brain metastases at any time during their disease course was similar, and the median number of treatments received by each group was two ().
Demographic and clinicopathological characteristics of ALK-positive and ALK-negative patients
Patients who are EGFR-positive are a paradigm for successful targeting of a genetically defined subset of NSCLC. ALK positivity defines a new and distinct subset with similarities to EGFR-positive patients, in terms of clinicopathological features and responsive ness to TKIs. Therefore, we compared survival in ALK-positive versus ALK-negative, EGFR-positive patients, since the latter represent a well established, TKI-sensitive comparator population. First, we compared survival in crizotinib-treated, ALK-positive patients with that in EGFR-positive patients who received either gefitinib or erlotinib. As shown in , from the time of starting TKI therapy, survival was similar for crizotinib-treated, ALK-positive patients (median overall survival not reached [95% CI 17 months to not reached], 1-year overall survival 71% [95% CI 58–81], 2-year overall survival 57% [40–71]) compared with EGFR TKI-treated, EGFR-positive patients (median overall survival 24 months [95% CI 15–34], 1-year overall survival 74% [61–83], 2-year overall survival 52% [38–65]; p=0·786). Since only six (11%) of 56 ALK-positive patients received crizotinib first-line, whereas most EGFR-positive patients (44 [70%] of 63) received first-line EGFR TKI therapy, we also compared survival by line of TKI therapy. Among the subsets of 30 ALK-positive and 19 EGFR-positive patients who received TKI therapy as their second-line or third-line agent, overall survival from the time of TKI therapy was also similar (median overall survival not reached [95% CI 14 months to not reached] vs 15 months [12–32]; 1-year overall survival 70% [95% CI 50–83] vs 72% [46–87], 2-year overall survival 55% [33–72] vs 43% [20–64], respectively; p=0·578). Thus, ALK-positive patients given crizotinib have a similar overall survival to EGFR-positive patients given an EGFR TKI.
Overall survival for ALK-positive versus ALK-negative patients
We also assessed survival in ALK-positive patients versus wild-type controls, for whom there are generally no effective TKIs. Analyses of overall survival measured from the time of metastatic diagnosis or from the time of second-line therapy yielded similar results. As shown in , median overall survival from second-line therapy among ALK-positive patients who did not receive crizotinib (n=23) was 6 months (95% CI 4–17), whereas that of wild-type controls (n=125) was 11 months [8–15]; however, this difference was not significant (p=0·175), suggesting that ALK-positive controls might have similar survival to wild-type controls. By comparison, ALK-positive patients given second-line or third-line crizotinib had significantly better survival than wild-type controls (HR 0·49, 95% CI 0·27–0·91; p=0·020; ), suggesting that crizotinib-treated, ALK-positive patients have better survival than the general population of NSCLC patients. From time of metastatic diagnosis, the survival of 36 crizotinib-naive, ALK-positive controls did not differ significantly from that of the entire group of 253 wild-type controls, with a median overall survival of 20 months (95% CI 13–26) versus 15 months (13–17; HR 0·77, 95% CI 0·50–1·19; p=0·244; ).
Comparing the survival of ALK-positive controls versus wild-type controls is potentially complicated by the fact that ALK-positive patients had distinct clinicopathological features (). The most important feature was never or light smoking status, a well-established prognostic factor. Therefore, we compared ALK-positive controls, most of whom were never or light smokers, with the subset of wild-type controls who were never or light smokers. Among never or light smoking patients younger than 60 years, overall survival from the time of metastatic diagnosis was similar between 24 ALK-positive controls and 52 wild-type controls; median overall survival was 20 months (95% CI 13–26) versus 24 months (16–33; HR 1·01, 95% CI 0·55–1·85; p=0·978; ). Similar results were obtained from analysis of the subset of never or light smoking patients with adenocarcinoma histology (data not shown). Taken together, these results suggest that in the absence of crizotinib therapy, the survival outcome of ALK-positive patients is similar to that of clinically comparable NSCLC patients who are ALK-negative and EGFR-negative.