Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy

BACKGROUND: In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy. METHODS: External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting. RESULTS: Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately. CONCLUSION: Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls

Clinical validation of Guardant360 CDx as a blood-based companion diagnostic for sotorasib

OBJECTIVES Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Immunotherapy for head and neck cancer: latest developments and clinical potential

Head and neck squamous cell cancer (HNSCC) is a malignancy with a rapidly changing demographic profile, given the recent epidemic of human papilloma virus related cancers. Most patients present with locally advanced disease and receive combination therapeutic approaches with curative potential, albeit with significant toxicity. Up to a third of patients, however, will eventually develop recurrent or metastatic disease. The prognosis of such patients is dismal, as palliative treatment options remain limited. Immune-directed therapies offer a novel therapeutic strategy beyond cytotoxic chemotherapy and are currently being evaluated in a wide variety of malignancies. HNSCC is a particularly favorable disease for immunotherapy, as immune evasion and dysregulation have been shown to play a key role in the initiation and progression of HNSCC. This review focuses on the latest developments in immunotherapy in HNSCC, with a particular focus on checkpoint inhibitors, adoptive cellular therapies, and vaccines

Barriers to physical activity: a study of academic and community cancer survivors with pain

PurposeDespite the numerous benefits of physical activity (PA) for patients with cancer, many cancer survivors report challenges to participating in PA. The objectives of this study were (1) to assess barriers to PA and (2) to examine participant characteristics associated with modifiable barriers to PA among cancer survivors with pain.MethodsWe conducted a cross-sectional survey study at one academic medical center and 11 community hospitals. Participants completed the 12-item Physical Activity Barriers After Cancer (PABAC) instrument (Cronbach's alpha = 0.75). Multivariable regression models examined participant characteristics associated with PABAC scores with a higher score indicating more barriers to PA.ResultsAmong 662 survivors, 67% had moderate or severe pain (rating 4 or greater on a scale of 0 to 10). Seventy-five percent of survivors did not meet the American Cancer Society PA recommendations on average, and these individuals had higher mean PABAC scores (beta coefficient (β) = 2.02, 95% confidence interval (CI) 0.96-3.09, p &lt; 0.001). In adjusted analyses, cancer survivors who were non-white (β = 1.55, 0.28-2.82, p = 0.02), treated at a community hospital (β = 1.07, 0.09-2.05, p = 0.03), had surgery (β = 1.69, 0.69-2.69, p = 0.001), or within 12&nbsp;months of diagnosis (β = 1.15, 0.20-2.10, p = 0.02) reported greater barriers to PA.ConclusionsThe majority of cancer survivors with pain are not adequately participating in PA. Key demographic and clinical characteristics are associated with survivors' barriers.Implications for cancer survivorsEfforts to overcome specific barriers are needed to promote PA after a cancer diagnosis

Comparative Clinical Outcomes Between EGFR Ex20ins and Wildtype NSCLC Treated with Immune Checkpoint Inhibitors.

The activity of immune checkpoint inhibitors (ICIs) in NSCLC harboring EGFR exon 20 insertion mutations (ex20ins) has not been closely examined due to the frequent exclusion of patients with EGFR mutations from large immunotherapy-based NSCLC trials. A real-world, retrospective study was conducted to compare outcomes of ICI-treated patients with EGFR ex20ins and wildtype NSCLC (wt-NSCLC; defined as EGFR and ALK test negative). Patients with advanced NSCLC from the Flatiron Health database (2015-2020) were included in the analysis. Real-world time to next therapy (rwTTNT) and overall survival (rwOS), stratified by ICI initiation line of therapy, were the prespecified primary and secondary endpoints, respectively. Among 59 patients with EGFR ex20ins NSCLC and 5365 with wt-NSCLC, ICI treatment was received as first-line therapy in 25% and 39%, respectively. Patients with EGFR ex20ins had a 58% increased risk of shorter time to next-line therapy compared with wt-NSCLC (adjusted hazard ratio of 1.58 [95% confidence interval [CI], 1.2-2.1]; P = .0012). The median rwTTNT for first ICI line was 3.7 months (95% CI, 3.0-4.9) for EGFR ex20ins NSCLC compared with 5.8 months (95% CI, 5.6-6.0) for wt-NSCLC. No meaningful difference in rwOS between the groups was observed. ICI therapy may be less effective for patients with EGFR ex20ins compared with wt-NSCLC. Consistent with prior data on exon 19 deletion and L858R substitution, tumors harboring ex20ins appear to be less responsive to immune checkpoint inhibition than wt-NSCLC

Comparative Clinical Outcomes Between EGFR Ex20ins and Wildtype NSCLC Treated with Immune Checkpoint Inhibitors

INTRODUCTION: The activity of immune checkpoint inhibitors (ICIs) in NSCLC harboring EGFR exon 20 insertion mutations (ex20ins) has not been closely examined due to the frequent exclusion of patients with EGFR mutations from large immunotherapy-based NSCLC trials. PATIENTS AND METHODS: A real-world, retrospective study was conducted to compare outcomes of ICI-treated patients with EGFR ex20ins and wildtype NSCLC (wt-NSCLC; defined as EGFR and ALK test negative). Patients with advanced NSCLC from the Flatiron Health database (2015-2020) were included in the analysis. Real-world time to next therapy (rwTTNT) and overall survival (rwOS), stratified by ICI initiation line of therapy, were the prespecified primary and secondary endpoints, respectively. RESULTS: Among 59 patients with EGFR ex20ins NSCLC and 5365 with wt-NSCLC, ICI treatment was received as first-line therapy in 25% and 39%, respectively. Patients with EGFR ex20ins had a 58% increased risk of shorter time to next-line therapy compared with wt-NSCLC (adjusted hazard ratio of 1.58 [95% confidence interval [CI], 1.2-2.1]; P = .0012). The median rwTTNT for first ICI line was 3.7 months (95% CI, 3.0-4.9) for EGFR ex20ins NSCLC compared with 5.8 months (95% CI, 5.6-6.0) for wt-NSCLC. No meaningful difference in rwOS between the groups was observed. CONCLUSIONS: ICI therapy may be less effective for patients with EGFR ex20ins compared with wt-NSCLC. Consistent with prior data on exon 19 deletion and L858R substitution, tumors harboring ex20ins appear to be less responsive to immune checkpoint inhibition than wt-NSCLC

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) account for ≤ 12% of all EGFR-mutant nonsmall cell lung cancers. We analysed real-world datasets to determine the frequency of ex20ins variants, and the ability of polymerase chain reaction (PCR) and next-generation sequencing (NGS) to identify them. Three real-world United States NGS databases were used: GENIE, FoundationInsights, and GuardantINFORM. Mutation profiles consistent with in-frame EGFR ex20ins were summarized. GENIE, FoundationInsights, and GuardantINFORM datasets identified 180, 627, and 627 patients with EGFR ex20ins respectively. The most frequent insertion region of exon 20 was the near loop (~ 70%), followed by the far loop (~ 30%) and the helical (~ 3-6%) regions. GENIE, FoundationInsights, and GuardantINFORM datasets identified 41, 102, and 96 unique variants respectively. An analysis of variants projected that ~ 50% of EGFR ex20ins identified by NGS would have been missed by PCR-based assays. Given the breadth of EGFR ex20ins identified in the real-world US datasets, the ability of PCR to identify these mutations is limited. NGS platforms are more appropriate to identify patients likely to benefit from EGFR ex20ins-targeted therapies

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy.

In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy. External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting. Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately. Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls