BackgroundAlthough EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade.Patients and methodsWe retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations.ResultsCompared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history.ConclusionsEGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.
Abstract Rationale We aimed to evaluate the impact of daily cat exposure in cat allergic asthmatics by both clinical symptom and immunological measures. Methods Twenty adults with history of cat-induced asthma and rhinitis, positive serum cat dander-specific IgE (sIgE>0.35kU/L) and Skin Prick Test (SPT) were enrolled at a 1:1 ratio according to cat ownership. For comparison, cat extract- and Fel d1- specific basophil sensitivity test (BST), serum sIgE, sIgG4 and SPT were measured on Day 1 and 28; ambulatory spirometry and symptom measures were obtained daily. Feld1 and 4-reactive CD4+ T cells were profiled using a CD154 upregulation assay. Results Cat owners had higher clinical symptom scores & medication use and a trend toward lower FEV1 vs. those not living with cats. Significantly higher levels of cat dander sIgG4 were observed among cat owners, but no significant difference was observed for cat-dander sIgE or SPT. All subjects tested positive on BST to Fel d1 and cat dander. Cat-ownership was associated with reduced basophil sensitivity to Fel d1, but had positive BST to Fel d4 and 7. T-cell response to Fel d1 and 4 were differentially polarized, with Fel d1 responses strongly polarized toward Th2 in both groups. No significant correlation was observed between basophil and T cell responses against cat allergen components. Conclusions Cat allergic subjects living with a cat demonstrated reduced pulmonary function and greater clinical symptom severity, despite higher medication use and sIgG4. An immunological difference between cat-owners vs. non cat-owners was detected by basophil assay but not by T-cell response.
<div>AbstractPurpose:<p><i>EGFR</i> exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer–associated <i>EGFR</i> mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown.</p><p><b>Experimental Design:</b> We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.</p>Results:<p>We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.</p>Conclusions:<p>These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.</p></div>
EGFR exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer-associated EGFR mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown.Experimental Design: We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.
Background: Linvoseltamab is a BCMA×CD3 bispecific antibody with encouraging efficacy and a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (Bumma et al. ASH 2022). Aims: Two Phase (Ph) 2 full dose cohorts (50 mg and 200 mg) in the LINKER-MM1 (NCT03761108) trial were studied to optimize dose selection. Methods: Ph 2 enrolled adults with MM who progressed on/after ≥3 lines of therapy (LoT) including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody (Ab), or were at least triple class (IMiD/PI/anti-CD38 Ab) refractory. A protocol amendment permitted pts who progressed during 4–12 weeks on 50 mg to dose escalate to 200 mg. Primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DoR) and minimal residual disease status. Results: As of 1 Sept 2022, 252 pts have enrolled (Ph 1: 73; Ph 2: 179 [200 mg: 75; 50 mg: 104]). Median age was 66 years (range 37–90), 12% had extramedullary plasmacytomas, 12% high-risk cytogenetics, 37% bone marrow plasma cell percentage (BMPC) ≥50%. Median soluble BCMA concentration (sBCMA) was 0.43 mg/L (range, 0–10.2), median prior LoT: 5 (range 1–16), and 81% were ≥triple class refractory. Numerically higher efficacy was observed with 200mg, including in high disease burden subgroups; ORR was 64% (200 mg cohort; n=58, includes 12 Ph 1 pts) and 50% (50 mg cohort; n=104). Subgroup analyses showed higher ORR in the 200 mg cohort versus 50 mg for sBCMA ≥0.4 mg/L, (52% vs 37%) BMPC >67% (64% vs 35%) and revised ISS stage III (71% vs 27%). Median DoR was not reached for both cohorts (median follow-up: 2.3 months [200 mg], 4.7 months [50 mg]). Probability of maintaining response at 6 months was 89% (200 mg) and 85% (50 mg). Out of 8 pts who progressed on 50 mg and dose escalated to 200 mg, 6 (75%) achieved a response. Treatment-emergent adverse events (TEAEs) occurred in 95% (Grade [Gr] ≥3: 66%) of pts in the 200 mg cohort (n=87, includes 12 Ph 1 pts) and 100% (Gr ≥3: 80%) in the 50 mg cohort. The most common TEAEs were cytokine release syndrome (200 mg: 37% [Gr 3: 1%]; 50 mg: 53% [Gr 3: 2%]), fatigue (200 mg: 32% [Gr ≥3: 0]; 50 mg: 33% [Gr ≥3: 0]) and anemia (200 mg: 28% [Gr ≥3: 24%]; 50 mg: 40% [Gr ≥3: 36%]). Grade ≥3 ICANS occurred in 2 pts (2%) in the 200 mg cohort and 1 pt (1%) in the 50 mg cohort. TEAEs leading to treatment discontinuation occurred in 7% (200 mg cohort) and 8% (50 mg cohort) of pts. Infections occurred in 43% (Gr ≥3: 26%) in the 200 mg cohort and 59% (Gr ≥3: 31%) in the 50 mg cohort. Summary/Conclusion: Linvoseltamab 200 mg showed better efficacy compared with 50 mg, including in pts with high disease burden. The 200 mg dose had consistent efficacy across high-risk subgroups and induced responses in pts who progressed on 50 mg. Safety was consistent across Ph 2 doses. The recommended linvoseltamab dose for further development is 200 mg. Updated data with longer follow-up and complete enrollment of the 200 mg cohort will be presented at the meeting. Keywords: Plasma cells, Clinical trial, Bispecific, Multiple myeloma
