Start Your Search
MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
MA19.09 - Concurrent Mutations in STK11 and KEAP1 is Associated with Resistance to PD-(L)1 Blockade in Patients with NSCLC Despite High TMB (ID 11983)
16:10 - 16:15 | Author(s): Andrew Plodkowski
Targeted next generation sequencing (NGS) testing for lung cancer patients identifies recurrent patterns of co-mutations. STK11 is known to be associated with poor outcomes with immunotherapy. We have identified that STK11 is commonly co-mutated with KEAP1, but the impact of this pattern of co-mutation on response to immunotherapy is not known.a9ded1e5ce5d75814730bb4caaf49419 Method
We identified 308 patients with advanced lung cancer treated at Memorial Sloan Kettering Cancer Center who underwent NGS testing with MSK-IMPACT and received at least one dose of PD-(L)1 inhibitor. Progression free survival (PFS) and overall survival (OS) from treatment initiation of PD-(L)1 blockade were calculated using Kaplan-Meier methodology and compared using logrank method and t-test for continuous variables.4c3880bb027f159e801041b1021e88e8 Result
In a cohort of 308 patients with NSCLC treated with PD-(L)1 blockade, STK11 or KEAP1 mutations occurred frequently (23% and 22% respectively) and concurrent STK11 and KEAP1 mutations (STK11mut/KEAP1mut) were common (56% of all STK11 mutant patients and 13% of all lung cancers, Fisher’s test of association p<0.0001). Other common co-mutations with STK11 included KRAS (50%) and TP53 (48%). STK11mut/KEAP1mut patients had higher TMB than STK11wt/KEAP1wt patients (median 9.4 vs 6.1, Mann-Whitney p= 0.0002).
STK11mut/KEAP1mut (n=39) patients had diminished PFS and OS compared to patients with STK11wt/KEAP1wt (n=210) (PFS HR 1.5, p=0.02; OS HR 2.3, p=0.001). As context, outcomes in STK11mut/KEAP1mut patients were similarly poor to EGFR mutant patients (n=28) treated with PD-(L)1 blockade (PFS p=0.7) despite substantially different tumor mutation burden (9.4 vs 4.9 mut/Mb, p<0.0001). Among STK11mut/KEAP1mut patients, poor outcomes were unchanged irrespective of KRAS status (PFS p=0.8, OS p=0.5). Patients with mutations in STK11 alone (n=31) or KEAP1 alone (n=28) had outcomes that more closely mirrored STK11wt/KEAP1wt patients (PFS p=0.9 and 0.1 respectively, OS p=0.1 and 0.2 respectively).8eea62084ca7e541d918e823422bd82e Conclusion
KEAP1 plus STK11 co-mutation is a common event in NSCLC that is distinctly associated with poor outcomes with PD-(L)1 blockade despite otherwise favor molecular features.6f8b794f3246b0c1e1780bb4d4d5dc53
Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.
P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Presentations: 1
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
P1.01-76 - A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers (ID 13324)
16:45 - 18:00 | Author(s): Andrew Plodkowski
Therapeutic options for SQCLC patients are limited. The efficacy of platinum-based doublets, long the standard first-line treatments, has plateaued, with ORR=30%. Anti-tumor synergy between gemcitabine and albumin-bound paclitaxel (ABP) was demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase, leading to increased intratumoral gemcitabine (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.a9ded1e5ce5d75814730bb4caaf49419 Method
This was a Simon two-stage phase 2 study of ABP + gemcitabine in chemotherapy-naïve, PD-L1 low/unknown advanced SQCLC patients (NCT02525653). Primary endpoint: best ORR. H0=25% (≥6/17 responses) and HA=45% (≥16/41 responses). ABP (100mg/m2) + gemcitabine (1000mg/m2) was initially given on D1, D8, D15 of an every 4 week cycle for up to 6 cycles (A1). After clearing H0, the study was amended to a 3 week cycle (D1, D8 treatment) and to allow maintenance ABP after C4 (A2). All patients underwent NGS by MSK-IMPACT.4c3880bb027f159e801041b1021e88e8 Result
N=27 patients were evaluable for the primary endpoint. Median age=70, age ≥70=60%, female=30%, median KPS=80%, smokers=93%. 46% of patients had PD-L1 IHC <50% (0-20%). 54% were PD-L1 unknown. Grade ≥3 related AEs included: fatigue-13%, neuropathy-4%; diarrhea-4%; lung infection-4%, anemia-9%; decreased platelet count-4%, and decreased neutrophils (4%). Four patients (17%) experienced related SAEs including, separately, G3 febrile neutropenia, G3 WBC decrease, G3 thrombocytopenia, and G3 anemia.
ORR for the entire cohort was 63% (Figure 1). ORR in A2= 71% (10/14). 8 patients in A1 had dose modifications resulting in equivalency to the A2 schedule. ORR in the A2+A1 dose modified cohort=73% (16/22), meeting the primary endpoint early. Median PFS=8mo; OS not yet mature.
ABP + gemcitabine is an effective and well-tolerated regimen in patients with untreated advanced SQCLC with a response rate exceeding that associated with platinum regimens and first-line immunotherapy.6f8b794f3246b0c1e1780bb4d4d5dc53