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Waree Rinsurongkawong
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)
10:30 - 12:00 | Author(s): Waree Rinsurongkawong
- Abstract
- Presentation
Background
PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.
Method
Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.
Result
Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).
ConclusionKRAS
BRAF
Classic EGFR
EGFR exon 20
HER2
MDACC cohort
Patients – N
87
10 (V600E 3 / non-V600E 7)
28
25
15
RR – %
24.3
62.5
4.5b
10b
8.3
Median PFS – mo (95% CI)
2.76
(2.23-3.30)
7.37 (not estimable)a
1.78 (1.18-2.37)
2.73 (1.71-3.75)
1.88 (1.63-2.12)
FH-CGDB
Patients – N
503
68 (V600E 32 / non-V600E 36)
52
42
25
Median rwPFS -
mo (95% CI)
3.55
(3.15-4.24)
6.0
(2.89-11.6)
2.17b
(1.77-2.63)
2.66b
(2.23-5.13)
1.87b (1.31-4.34)
Median rwOS – mo (95% CI)
10.28
(8.51-12.02)
16.07
(8.64-NA)
5.29b
(3.25-17.68)
9.89b
(3.68-20.86)
10.81
(4.17-NA)
FoundationCore cohort – N
NA
188 (V600E 74 / non-V600E 114)
386
96
57
TMB – mean (mut/Mb)
NA
10.6a
3.7
3.8
5.8
PD-L1 TPS ≥ 50% (%)
NA
36a
19
23
16
a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.
NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.
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MA14 - The Adequate MTarget Is Still the Issue (ID 140)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Diego Signorelli, Juergen Wolf
- Coordinates: 9/09/2019, 15:45 - 17:15, Hilton Head (1978)
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MA14.10 - Clinical Outcomes in Metastatic Squamous Lung Cancer with Targetable Driver Alterations (Now Available) (ID 527)
15:45 - 17:15 | Author(s): Waree Rinsurongkawong
- Abstract
- Presentation
Background
Genomic profiling is not routinely performed for metastatic squamous (SCC) and adenosquamous (ASC) NSCLC. However molecular profiling may be ordered if demographic features suggest a higher likelihood of a targetable driver alteration (e.g. never or remote smoking history). Response and survival data are scant in pts with actionable alterations treated with targeted therapy.
Method
We reviewed the clinical data and molecular profiling (FISH, PCR, tissue NGS, ctDNA) of metastatic SCC and ASC pts treated at our institution from Feb 2010-Dec 2018. Pts with typical sensitizing mutations in EGFR or BRAF V600E or fusions in ALK or ROS1 treated with matched targeted therapy for ≥ 2 months were included in this analysis. Response assessment was based on RECIST v1.1.
Result
Among 261 metastatic SCC or ASC pts with available molecular profiling, 16 total pts (6%) were found to have actionable targets, consisting of 13 SCC and 2 ASC (median age 53, 81% female, 88% never-smoker). The distribution of driver alterations in this cohort was 56% (9/16) EGFR ex19del/L858R/G719A, 38% (6/16) ALK fusion, and 6% (1/16) BRAF. The overall objective response rate (ORR) and median progression free survival (PFS) to targeted therapy was 69% and 5.2 months respectively. By mutational subgroup, ORR was 67% (6/9) for EGFR, 67% (4/6) for ALK, and 100% (1/1) for BRAF. Median PFS was only 4.5 months (95% CI 3.0 – 6.0) for EGFR pts and 2.8 months (95% CI 0 – 6.4) for ALK pts, and the lone BRAF pt had a PFS of 8.5 months. In EGFR pts with available NGS, co-mutations in TP53 (75% [6/8]) and PIK3CA (38% [3/8]) were seen at rates higher than previously reported in EGFR+ ADC (TP53 55%, PIK3CA 12%; Blakely et al, Nat Gen 2017). In ALK pts with available NGS, co-mutations in TP53 (80% [4/5]) were also higher than recently reported in ALK+ ADC (24%; Kron et al, Ann Oncol 2018).
Conclusion
Despite initial responses comparable to those previously reported in ADC, matched targeted therapy in pts with SCC and ASC histology is associated with shorter PFS. A higher prevalence of adverse co-mutations such as TP53 and PIK3CA may contribute to early targeted therapy resistance in these histologies. These findings may have implications for the use of targeted therapy in squamous lung cancer.
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MA19 - Looking at PROs in Greater Detail - What Patients Actually Want and Expect (ID 147)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:Joaquim Bosch-Barrera, Virginia Calvo De Juan
- Coordinates: 9/10/2019, 11:30 - 13:00, Interlaken (1988)
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MA19.03 - Differences in Symptom Burden Between Responsive and Progressive Disease in Advanced Non-Small Cell Lung Cancer (aNSCLC) (Now Available) (ID 845)
11:30 - 13:00 | Author(s): Waree Rinsurongkawong
- Abstract
- Presentation
Background
We have established a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) to assess how immunotherapy impacts treatment choice, clinical outcomes, and patient-reported outcomes (PROs) of aNSCLC. Our aim in this analysis was to assess the ability of the MDASI-LC to differentiate between patients who are responding or who are progressing during treatment.
Between May 2017 and December 2018, patients with aNSCLC at a single institution were enrolled in ANCHoR and completed the MDASI-LC prior to therapy (PTT) and at routine clinic visits. The MDASI-LC consists of 16 symptom severity and 6 interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). MDASI-LC scores from PTT to first recorded response determination (FRD) were compared by response group using linear mixed modeling (LMM).
Result
One hundred one patients completed the MDASI-LC PTT and at FRD. Mean patient age was 63.8 years (standard deviation = 10.29) and 55% were males. Fifty percent of patients received chemotherapy (CTX), 22% immunotherapy (IM), 19% CTX+IM or angiogenesis inhibitor, and 9% targeted therapy. Median time from PTT to FRD was 105 days (lower quartile = 63, upper quartile = 224). Forty-six percent of patients had a complete or partial response (RECIST criteria CR, PR), 14% had stable disease (RECIST SD), and 41% progressed (RECIST PD). LMM showed progressing patients had significantly more fatigue (estimated effect [est] =1.39; p = 0.031), sleep disturbance (est=1.37; p = 0.046), and drowsiness (est=1.33; p = 0.037) and reported significantly more interference with work (est=1.67; p = 0.016) over time than responding patients.
Conclusion
The MDASI-LC differentiated the symptom burden of patients with responding disease from that of patients with progressive disease. Patients with progressive disease had more fatigue, disturbed sleep, drowsiness, and greater interference with work than those with responsive disease. Further research is needed to determine if the MDASI-LC can predict response to therapy in patients and may be useful in delineating treatment benefit.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-08 - Activity of Poziotinib and Other 2nd-Gen Quinazoline EGFR TKIs in Atypical Exon18 and Acquired Osimertinib Resistance Mutants (ID 2694)
09:45 - 18:00 | Author(s): Waree Rinsurongkawong
- Abstract
Background
In EGFR, exon 18 encodes for the P-loop (L718-V726), and mutations in this region (G719S/A, L718Q/V, G724S) are known to reduce sensitivity to osimertinib and first-generation EGFR TKIs. Osimertinib resistance is associated with a number of acquired mutations in exons 19 and 20 (S784F, L747S, C797S and L792H). We investigated the frequency and drug sensitivity of these and other osimertinib-resistant EGFR mutations
Method
We generated ~50 different Ba/F3 cell line models expressing classical and/or atypical EGFR mutations (exons 18-21) and evaluated the transforming ability and sensitivity to 14 EGFR TKIs including non-covalent (first-generation), afatinib, dacomitinib, and poziotinib (quinazoline and covalent, second-generation), and covalent T790M-specific (third-generation) inhibitors. Impact of atypical mutations was analyzed by in silico modeling.
Result
We found 3.6% (N=32/895) of EGFR-mutant patients had atypical, exon 18, P-loop mutations in the MD Anderson GEMINI database. Modeling of classical EGFR mutations revealed osimertinib has distinct interactions between the solvent front of osimertinib and residues within the P-loop of EGFR, whereas second-generation quinazoline TKIs, such as poziotinib, extend into the pocket, near T790, lacking these interactions. Mutations in the P-loop were predicted to shift osimertinib out of alignment with V726 and F723, causing resistance to osimertinib but not quinazoline-based TKIs. Atypical exon 18 mutations (G719S/A, L718Q/V, G724S) had IC50 values of 113.6nM, 1.6nM, and 137.5nM for first-, second-, and third-generation TKIs, respectively. Second-generation TKIs inhibited G719S/A-T790M mutations at concentrations 2-fold lower than third-generation TKIs (IC50 = 23.4nM and 46nM). Osimertinib-resistance mutations (L747S, S784F, C797S, L792H) co-occurring with classical sensitizing mutations (L858R or ex19del) had IC50 values of 56.8nM, 1.4nM, and 996nM to first, second and third-generation inhibitors. Of the second-generation TKIs tested, poziotinib was the most potent for atypical exon 18 P-loop mutations; G719S/A-T790M mutations; and classical mutants with acquired osimertinib-resistance mutations (IC50= 0.4nM, 3.2nM, 0.8nM).
Conclusion
Exon 18 atypical P-loop mutations and osimertinib-resistance mutations demonstrated high sensitivity to second-generation quinazoline TKIs, compared to first- and third-generation inhibitors. Mutations in the P-loop of EGFR confer resistance to third-generation TKIs by destabilizing solvent front interactions of the molecule, and osimertinib-resistance mutations interfere with covalent binding at C797. Second-generation TKIs, especially poziotinib, are potent inhibitors of these mutations because they have increased hydrophobic interactions at the back of the drug binding cleft that are retained without covalent binding. Together, these data indicate that poziotinib and other second-generation TKIs may be useful for the treatment of NSCLC patients with atypical P-loop and selected osimertinib-resistant EGFR mutations.
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-31 - Body Mass Index Relating to Patient-Reported Symptoms in First-Line Treatment of Metastatic Non-Small Cell Lung Cancer (ID 2619)
09:45 - 18:00 | Author(s): Waree Rinsurongkawong
- Abstract
Background
Patient-reported outcomes (PROs) provide information on patient treatment experience. Our aim in this analysis was to assess the longitudinal relationship between body mass index (BMI) with patient-reported symptom severity and interference during treatment.
Method
Between May 1, 2017 and December 7, 2018, patients with mNSCLC at a single institution were enrolled in a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) and completed the MDASI-LC prior to start of therapy and at routine clinic visits. MDASI-LC consists of 16 symptom severity and 6 symptom interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). BMI was measured at the same schedule as MDASI-LC. Mixed-effects models were used to examine the longitudinal association between BMI and symptom levels during treatment.
Result
103 patients completed the MDASI-LC prior to start of therapy and at least 2 follow-up assessments. Mean patient age was 64.3 years (standard deviation = 11.5) and 50% were males. 22% of patients received chemotherapy (CTX), 34% immunotherapy (IM), 23% CTX+IM or angiogenesis inhibitor, and 20% targeted therapy. The median pre-treatment BMI was 25.2 (inter quartile range, 5.2). BMI did not change during treatment and no significant difference was found among treatment groups. Compared with the obese group (BMI≥30), the overweight group (25≤BMI<30) experienced lowest levels of fatigue (estimation(est)=-1.23, standard error (SE)=0.49, p=0.016), disturbed sleep (est=-1.66, SE=0.49, p=0.002), distress (est=-0.90, SE=0.40, p=0.030) and less interference on mood (est=-1.03, SE=0.46, p=0.030) and interference with walking (est=-1.50, SE=0.51, p=0.005). The normal group (BMI<25) demonstrated lower levels of fatigue (est=-1.05, standard error (SE)=0.47, p=0.032) and disturbed sleep (est=-1.15, SE=0.47, p=0.018), compared with the obese group.
Conclusion
For patients with mNSCLC, obesity was related with higher symptom burden during active treatment. This analysis provides pilot data for future studies on balanced weight control and patients’ wellbeing during cancer treatment.