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PURPOSE National Cancer Institute–Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2-activating mutations. METHODS Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute–Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction > 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates. RESULTS A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received > 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor–positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor–positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common (> 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events. CONCLUSION Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.

Purpose: We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the AACR Project GENIE Biopharma Collaborative (BPC). Experimental Design: 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMMÔ data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies. Results: In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%) and oncogenic fusions (ALK, RET and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 mo (95% confidence interval (CI) 14.9,19.5 mo). For second-line therapies, mOS was 9.2 mo (95% CI 7.5,11.3 mo) for immune checkpoint inhibitors (ICI) and 6.4 mo (95% CI 5.1,8.1 mo) for docetaxel +/- ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 mo; 95% CI 2.2, 2.8) and median real-world PFS based on imaging reports (2.2 mo; 95% CI 1.7,2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR 0.85, p=0.03, n=247 patients). Conclusions: The GENIE BPC cohort provides comprehensive clinico-genomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.

Includes Supplemental Figure S1 and Supplemental Tables S1-S7

Raw cell counts of FISH gene probes for (1) primary breast tumors, (2) metastatic sites, (3) pre- and post-treatment [Hungarian sample], and (4) TNBC cases.

Supplemental Methods. Supplemental Table 1: ââ,¬â€¹Genomic Data Characterization by Center. Supplemental Table 2: ââ,¬â€¹Gene Panels Submitted by Each Center. Figure S1: Number of putative germline SNPs per sample, before and after uniform germline filtering. Figure S2ââ,¬â€¹. Distribution of total somatic mutation burden per sample stratified by sequencing panel. Figure S3: ââ,¬â€¹Log-scale comparison of mutation frequencies at hotspot sites between GENIE (data aggregated from all sequencing panels) and cancerhotspots.org (CHS) using a binomial test. Figure S4:ââ,¬â€¹ Comparison of mutation frequencies at hotspot sites in each GENIE sequencing panel with cancerhotspots.org (CHS) using a binomial test.

Table S4

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2− cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC.Significance:The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659

File with the supplementary material & methods, supplementary tables and supplementary figure.

AACR GENIE Data Guide

Supplementary Tables and Figures

Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.

AKT inhibitors have promising activity in AKT1E17K-mutant estrogen receptor (ER)–positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1E17K-mutant (n = 153) and AKT1–wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1–wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology.Significance:We delineate the natural history of a rare genomically distinct cancer, AKT1E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.See related commentary by Castellanos and Baxi, p. 490.

PURPOSE To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials. METHODS Plasma samples were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria. RESULTS A total of 162 plasma samples were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma samples (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.77; P < .01) and overall survival (HR, 0.54; 95% CI, 0.3 to 0.96; P = .03) compared with an increase. These differences were more marked if there was a >50% decrease in mVAF for both progression-free survival (HR, 0.29; 95% CI, 0.13 to 0.62; P < .001) and overall survival (HR, 0.23; 95% CI, 0.09 to 0.6; P = .001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients. CONCLUSION A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials.

ALPHABET is a randomized phase III trial assessing alpelisib + trastuzumab with or without fulvestrant in previously treated HER2-positive PIK3CA-mutated advanced breast cancer. Patients will be included in two cohorts according to hormone receptor (HR) status. In the experimental arms, patients in the HR-negative cohort will receive trastuzumab + alpelisib, and patients in the HR-positive cohort will receive the same treatment plus fulvestrant. Patients in the control arms will receive trastuzumab + physician’s choice chemotherapy (eribuline, capecitabine or vinorelbine). Key eligibility criteria include 1–4 previous lines of anti-HER2 therapy and prior trastuzumab emtansine. The primary end point is investigator-assessed progression-free survival. The study aims to recruit a total of 300 patients.

Background: Despite the availability of multiple HER2-targeted therapies, most patients (pts) with advanced HER2-positive BC experience disease progression, and an unmet medical need remains. Zanidatamab (zani) binds to HER2 across a range of expression levels and induces formation of receptor clusters, resulting in receptor internalization and downregulation that affect signal transduction. Zani potently activates antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. In this ongoing phase 1 study (NCT02892123), data from BC pts treated with zani monotherapy have been previously reported. Here, we evaluated the safety and antitumor activity of zani in combination with chemo in HER2-positive BC pts. Methods: Pts with locally advanced and/or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/fluorescence in situ hybridization+) BC who received prior trastuzumab (tras), pertuzumab (pert), and T-DM1 were enrolled. Eligibility criteria included Eastern Cooperative Oncology Group performance status ≤1 and adequate organ function. Prior history of treated stable brain metastases was allowed. Zani (20 mg/kg Q2W or 30 mg/kg Q3W) was administered in combination with paclitaxel (pac), capecitabine (cap), or vinorelbine (vin). Zani + chemo was continued until disease progression or toxicity; if chemo was discontinued due to toxicity, zani treatment could be continued. Primary endpoints were safety and tolerability assessments; secondary efficacy endpoints included objective response rate (ORR) and disease control rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) per RECIST v1.1, and progression-free survival (PFS). Clinical benefit rate (CBR) was defined as SD ≥24 weeks or best overall response of CR or PR. Results: As of 3 May 2021, 20 HER2-positive BC pts had enrolled (zani + pac, n=4; zani + cap, n=9; zani + vin, n=7). Ten pts were hormone receptor positive (data available for 19 pts), and 7 pts had a prior history of brain metastases. Median age was 53 years (range, 38-72), with median prior systemic therapies of 4.5 (range, 2-7) and median of 2 regimens in the metastatic setting. Pts received a median of 3 prior HER2 regimens; all pts received tras and T-DM1, 17 received pert, and 6 received tyrosine kinase inhibitors. In the 16 response evaluable (measurable disease and either post-baseline assessments or earlier death/progression) pts, confirmed ORR was 37.5% (with 1 additional response pending confirmation), CBR was 50%, and DCR was 81.3%. Median duration of response was not reached (range, 1.8+ to 16.8+ mo), with 4 of 6 confirmed responses ongoing. Among all pts (n=20), the most common (≥30% of pts) zani- and/or chemo-related adverse events (AEs) were diarrhea (65%), nausea (45%), peripheral neuropathy (35%), and fatigue (30%). One pt experienced grade 3 diarrhea leading to dose reduction of zani, and 1 pt discontinued zani due to AEs (abdominal pain and nausea, both grade ≤2). Four grade 4 AEs were observed in 4 (20%) pts: neutrophil count decreased (2 pts) and neutropenia (1 pt), all related to chemo, and hyponatremia (1 pt, not related to study treatment). Serious AEs were observed in 2 (10%) pts (pleural effusion, 1 pt; pneumonitis and upper respiratory tract infection, 1 pt), none related to zani. No grade 5 AEs were reported. Conclusions: Zani in combination with chemo is well tolerated, with encouraging and durable antitumor activity in heavily pretreated (including prior tras, pert, and T-DM1) pts with HER2-positive BC. These data support further investigation of zani as a novel therapeutic for these pts. The cap and vin cohorts continue to enroll, and additional cohorts are evaluating zani ± chemo in combination with tucatinib. Citation Format: Philippe L Bedard, Seock-Ah Im, Elena Elimova, Sun Young Rha, Rachel Goodwin, Cristiano Ferrario, Keun-Wook Lee, Diana Hanna, Funda Meric-Bernstam, Jose Mayordomo, Murali Beeram, Erika Hamilton, Jorge Chaves, Melody Cobleigh, Tony Mwatha, Joseph Woolery, Do-Youn Oh. Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): Results from a phase 1 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-07.

Purpose:Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.Patients and Methods:Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.Results:Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy.Conclusions:Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.

Supplementary Materials

Exposure to taselisib

Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. Clin Cancer Res; 22(6); 1348–55. ©2015 AACR.

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Supplementary Tables

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Table S1 provides a summary of the genetic association results in the European only cohort

Supplementary Methods

redacted protocol

Supplementary Figures S1, S2, S3 and Tables S1, S2

Supplementary Figure 1 Total Nesvacumab (REGN910) and Total Ang2 vs Time (cycle 1) following IV infusion in Patients. Supplementary Figure 2 Serum levels of ESM1, SDF-1, PLGF-1 and sVCAM-1 following Nesvacumab (REGN910) treatment. Supplementary Figure 3 Correlative analysis of baseline serum Ang2, ESM-1, SDF-1 ,PIGF and cVCAM-1 and treatment duration. Supplementary Figure 4 Correlative analysis of baseline Ang2 in tumor vessels and treatment duration/response. Supplementary Figure 5 Ang2 and VEGF-A protein levels in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 6 Biomarker analysis of archival tumor tissue. Supplementary Figure 7 Microvascular density in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 8 Tumor cell proliferation in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 9 TIE-2 protein levels associated with tumor vessels pre and post treatment with Nesvacumab (REGN910)

Figure S4 provides examples of audiogram configurations

Participant PIK3CA-mutation central testing results

Supplementary Table 1. Summary of the Most Common (>10%) Treatment-Emergent Adverse Events

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Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection.Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

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Purpose:We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor–positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification.Experimental Design:We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor–positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type.Results:A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group.Conclusions:ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

Supplementary Table S1. Treatment dose, duration, interruption and reduction. Supplementary Table S2A. Performance of the FGF23 ELISA, Kainos Laboratories Inc., cat# CY4000. Supplementary Table S2B. Concentration range of FGF23 in serum and plasma samples. Supplementary Table S2C. ddPCR assays used for determination of FGFR1 CNV. Supplementary Figure S1. A) FINESSE study design. B) Supplementary Figure S1B. FINESSE CONSORT diagram. Supplementary Figure S2. FISH screening results for FGFR1, CCND1/11q and FGF3,4,19. All samples were screened for both FGFR1 and CCND1/11q. Only samples positive for CCND1/11q amplification were assessed for FGF3,4,19 amplification. Of these, 1 patient was not assessed for FGF3,4,19 at the request of the site. 3 patients assessed as FGF3,4,19 amplified by additional evalution criteria to those described in the Methods section, with >50% of tumour cells showing {greater than or equal to}5 gene signals/nucleus. Supplementary Figure S3. Progression-free survival by A) FGFR1 amplification status by FISH and B) FGFR1 expression by IHC. Supplementary Figure S4. Expression of endothelial FGF2 and Ki67 presented by trial cohort. Supplementary Figure S5. Progression free survival by A) endothelial FGF2 and B) endothelial Ki67 expression.

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