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Viola Zhu
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.07 - Clinical Outcomes and ALK Resistance Mutations in ALK+ Non-Small Cell Lung Cancer According to EML4-ALK Variant (ID 8255)
16:25 - 16:30 | Author(s): Viola Zhu
- Abstract
- Presentation
Background:
Advanced ALK+ non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes among patients treated with ALK TKIs vary, and the clinical benefit of TKI therapy is limited due to acquired resistance. To date, emerging data suggest that the specific EML4-ALK variant may impact clinical outcome, but whether variant is associated with mechanisms of TKI resistance is unknown.
Method:
We identified 108 advanced ALK+ NSCLC cases with known ALK fusion variants. Progression-free survival (PFS) on ALK TKIs and resistance mechanisms were retrospectively evaluated according to ALK variant.
Result:
The 108 ALK+ cases consisted of: 42 (39%) EML4-ALK v1 (E13;A20), 8 (7.4%) v2 (E20;A20), 45 (41.7%) v3 (E6;A20), 3 (2.8%) v5 (E2;A20), 4 (3.7%) v5’ (E18;A20), 1 (0.9%) v7 (E14;A20), and 5 (4.6%) non-EML4-ALK variants. Given the small numbers of non-v1/v3 cases, v1 and v3 cases were selected for further analysis. Among the 21 v1 and 25 v3 cases treated with first-line crizotinib, there was no significant difference in PFS (HR = 0.81 [95% CI, 0.42-1.57], p = 0.526). Similarly, there was no difference in PFS on second-generation ALK TKIs among 35 v1 and 35 v3 patients who received ceritinib, alectinib, or brigatinib following first- or later-line crizotinib (HR = 1.32 [95% CI, 0.77-2.26], p = 0.308). Interestingly, among 12 v1 and 17 v3 patients who received the third-generation TKI lorlatinib after failure of a second-generation TKI, v3 was associated with significantly longer PFS than v1 (HR = 0.250 [95% CI, 0.09-0.72], p = 0.006). From our cohort, we identified 11 v3 and 14 v1 post-crizotinib biopsies. No difference was noted in the presence of ALK resistance mutations (27% and 21%, respectively; p = 1.000). In contrast, among 30 v3 and 18 v1 post-second generation TKI biopsies, ALK resistance mutations were more common among v3 vs v1 cases (66% vs 44%, respectively; p = 0.147). Furthermore, the ALK G1202R solvent front mutation occurred more frequently in v3 vs v1 (47% vs 0%, respectively; p = 0.001).
Conclusion:
Our findings suggest that EML4-ALK variants 1 and 3 may not be associated with significantly different PFS outcomes on crizotinib or second-generation ALK TKIs. However, ALK resistance mutations, particularly G1202R, occur more frequently in v3 vs v1 post–second generation TKI. Patients with this variant may therefore derive particular benefit from third-generation, pan-inhibitory ALK TKIs. Larger, prospective studies will be needed to confirm these findings.
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MS 02 - Ethnic Differences: Biology or Myth (ID 524)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
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MS 02.05 - Is Ethnicity a Prognostic Factor in Lung Cancer (ID 7731)
12:00 - 12:15 | Presenting Author(s): Viola Zhu
- Abstract
- Presentation
Abstract:
Is ethnicity a prognostic factor in lung cancer? If so, it is due to differences in tumor genomic characterization, in response to treatment or some other factors? Do patients with different ethnic backgrounds experience different tolerability to therapy? How about culture factors, life style variants or environmental exposures that may pay a role in outcomes? The results from the Lung Cancer Mutation Consortium did not show significant differences in survival between Whites, African Americans, Asians, and Latinos with adenocarcinomas. However, the number of non-Whites in this study was relatively small. The rate of oncogenic mutations was highest among Asians (81%) followed by Latinos (68%), Whites (61%), and African Americans (53%). It is well documented that the frequency of EGFR mutations is higher in Asians (50-60%) than in Whites (10-20%). In fact, based on a case series from a single institution in China, 90% of lung adenocarcinomas from never smokers harbored these oncogenic mutations. Even in Asian current smokers with adenocarcinomas, the frequency of EGFR mutations could be as high as 35.3% as compared to 5.8% in White current smokers with the same histology. It remains unclear why Asians harbor such a high rate of EGFR mutations. A recent meta-analysis of genome-wide association studies of Asian never-smoking women with lung cancer has identified multiple genetic susceptibility loci, which may serve as a plausible explanation. As patients with oncogenic mutations have significantly better outcomes than those without, ethnicity does carry a prognostic value when it comes to Asians vs Whites. In terms of response to treatment, for patients with EGFR mutations, a meta-analysis of 7 randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) to chemotherapy did not show a clearly better PFS favoring EGFR TKIs for Asians (Hazard ratio [HR]: 0.36, 95% confidence interval [CI]: 0.31-0.42) than for non-Asians (HR: 0.42, 95% CI: 0.31-0.58). For patients with ALK rearrangements treated with crizotinib versus chemotherapy in PROFILE 1014, a slightly better PFS favoring crizotinib was seen for Asians (157 patients, HR: 0.44, 95% CI: 0.3-0.65) than for non-Asians (186 patients, HR: 0.53, 95% CI: 0.36-0.76), while the opposite was demonstrated with ceritinib in ASCEND-4 (Asians: 158 patients, HR: 0.66, 95% CI: 0.41-1.06; non-Asians: 202 patients, HR: 0.44, 95% CI: 0.3-0.66). In ALEX study, Asians (138 patients, HR: 0.46, 95% CI: 0.28-0.75) had a similar PFS favoring alectinib over crizotinib as non-Asians (165 patients, HR: 0.49, 95% CI: 0.32-0.75). With regards to immunotherapy, no conclusion can be drawn on outcomes between Asians (40 patients, HR: 0.35, 95% CI: 0.14-0.91) and non-Asians (265 patients, HR: 0.52, 95% CI: 0.38-0.72) in KEYNOTE-024 as the study enrolled significantly fewer Asians accounting for the wide range of confidence interval for PFS favoring pembrolizumab over chemotherapy. The discussion on potential differences between Asians and non-Asians in response to chemotherapy is beyond the scope of this mini-review, but it is unlikely that ethnicity would serve as a surrogate factor for efficacy and even tolerability to predict prognosis. Lastly, according to the American Cancer Society, African Americans continue to have higher death rates from lung cancer than Whites, but the gap has narrowed for men. For EGFR mutations, the frequency in African Americans as compared to Whites varied by reports. By using targeted massively parallel sequencing, Araujo et al. have suggested that genomic characterization of African Americans with non-small cell lung cancer (NSCLC) may not be significantly different from that of Whites. However, a pooled analysis done by the same group with a larger sample size has shown a different pattern of oncogenic mutations in African Americans than in Whites, although the frequency of EGFR or KRAS mutations was similar between the two groups. Interestingly, a study utilizing the Veterans Affairs Central Cancer Registry has shown that even though African Americans with NSCLC had worse prognostic factors than Whites, they had a better overall survival. These data suggest that disparity in outcomes between Africans Americans and Whites may be related to barriers to access rather than inherent biology. In summary, ethnicity plays a prognostic role in lung cancer between Asians and non-Asians largely due to the fact that Asians have a higher frequency of oncogenic mutations, which is clearly associated with better outcomes, whereas the disparities between African Americans and Whites are more likely to be driven by healthcare inequality leading to a poorer prognosis among African Americans with lung cancer. Endeavors should be undertaken to provide better access to care for ethnic minorities.
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