With platinum-based CTX, prognosis of patients (pts) with unfavourable CUP is poor; however, CGP may inform treatment strategies based on cancer genomics. The CUPISCO trial (NCT03498521) compared the efficacy and safety of molecularly guided therapy (MGT) vs standard platinum-based CTX in pts with newly diagnosed, unfavourable, non-squamous CUP. Pts had central eligibility review-confirmed CUP with ≥1 measurable lesion (investigator-assessed via RECIST v1.1). All had tumour tissue and/or blood CGP (Foundation Medicine, Inc.). After 3 induction CTX cycles, pts with disease control were randomised 3:1 to MGT (investigator’s choice from 12 regimens after molecular tumour board advice) or continuation with ≥3 more CTX cycles (category 1; shown here), stratified by gender and response to induction CTX. Pts with progressive disease received MGT (category 2). The primary endpoint was progression-free survival (PFS) in category 1 pts. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and disease control rate (DCR). Safety was also assessed. Exploratory endpoints included quality of life (QoL). From Jul 2018–Dec 2022, 436 category 1 pts were randomised: 326 to MGT; 110 to CTX. Median PFS (intent-to-treat population) was 6.1 months (95% confidence interval [CI] 4.7–6.5) with MGT vs 4.4 months (4.1–5.6) with CTX (hazard ratio [HR] 0.72; 95% CI 0.56–0.92; P=0.0079). Median OS was 14.7 (95% CI 13.3–17.3) vs 11.0 months (9.7–15.4), respectively (HR 0.82; 95% CI 0.62–1.09; P=0.1779), though OS data were immature at cutoff. ΔORR was 9.6% (95% CI 2.4–16.8, P=0.0141) in favour of MGT, with similar DoR in each arm (HR 0.95; 95% CI 0.33–2.72). ΔDCR was 4.7% (95% CI –6.4–15.9; P=0.3922) in favour of MGT. Adverse event rates were generally similar with MGT vs CTX; no difference in QoL was observed. In pts with newly diagnosed, unfavourable, non-squamous CUP who responded to induction CTX, CGP with MGT improved PFS. Early CGP and MGT should be considered the new standard of care for these pts.

BACKGROUND:Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis. METHODS:CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing. FINDINGS:From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy. INTERPRETATION:In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP. FUNDING:F Hoffmann-La Roche.

Supplementary Table 1 Downregulation of HER3 membrane protein expression in skin biopsies following treatment with lumretuzumab and cetuximab or erlotinib Supplementary Table 2 Change of tumor biomarkers in tumor biopsies following treatment with lumretuzumab and cetuximab or erlotinib

PDF file - 93K, Distribution of the PAM50 intrinsic subtypes based on RORP score groups.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

Supplementary Figure 1 Quantile plots of baseline membrane HER3 IRS score (A) and HER3 mRNA log expression (B) in baseline FFPE tumor biopsy samples from patients with known adeno- and squamous cell carcinoma histology Supplementary Figure 2 Quantile plots of baseline membrane HER3 immuno-reactive scores in fresh FFPE tumor biopsies from NSCLC patients with non-squamous or squamous histology Supplementary Figure 3 Quantile plots of baseline HRG mRNA log expression determined by qRT-PCR in FFPE tumor biopsies of adeno- and squamous cell carcinoma histology (data obtained using the HRG research assay) Supplementary Figure 4 Baseline HRG mRNA log expression in FFPE tumor biopsies, determined by qRT-PCR, in non-sqNSCLC and sqNSCLC (data obtained using the HRG prototype diagnostic assay). Dotted line indicates prior determined median HRG expression in sqNSCLC. Supplementary Figure 5 Best percentage change from baseline in sum of longest diameters of target lesions for patients in the dose escalation and extension phase of the cetuximab part (n = 38). Red bars indicate PD patients, blue bars SD patients, light green bars PR patients and dark green bars CR patients. Eleven patients were without target lesion assessment post baseline. Tumor type and lumretuzumab dose are indicated. * indicates patients who received previous EGFR-targeting therapy. a indicates a patient who received prior trastuzumab therapy. Supplementary Figure 6 Best percentage change from baseline in sum of longest diameters of target lesions for patients in the dose escalation phase and the two NRG1 fusion gene patients of the extension phase of the erlotinib part (n = 31). Red bars indicate PD patients, blue bars SD patients and green bars PR patients. Eight patients were without target lesion assessment post baseline. Tumor type and lumretuzumab dose are indicated. * indicates patients who received previous EGFR-targeting therapy. a indicates two patients with NRG1 gene fusion.

PDF file - 44K, Clinical-pathological comparison of the NOAH and the transNOAH gene expression (GEP) tumor samples.

PDF file - 105K, Ability of the high RORP group to predict pCR in 91 patients with clinically HER2-positive disease treated with trastuzumab-based chemotherapy in the ISPY-1, MDACC and XeNA studies.

Figure 1 Mean ({plus minus}SD) serum lumretuzumab profiles following multiple ascending doses from 100 mg up to 2000 mg Figure 2 Percentage change in standardized uptake value maximum from baseline as assessed by FDG-PET at (a) Cycle 1 Day 14 and (b) Cycle 4 Day 14 Table 1 Summary of baseline and change in HER3 expression measured by IHC in skin and tumor biopsy samples pre and post treatment with lumretuzumab Table 2 Summary of change in expression of HER3, HER2, EGFR and cMET in fresh tumor biopsies compared to primary archival samples Table 3 Peripheral blood immunophenotyping (T, B and NK cells and NK subsets) from patients dosed with 2000 mg lumretuzumab Table 4 Ex-vivo activation potential of peripheral NK lymphocytes for all patients at ba seline and following exposure to lumretuzumab in the 2000 mg dose cohort Table 5 Summary of tumor immune effector cell infiltration Table 6 Tumor response to treatment (RECIST)

PDF file - 102K, Clinical-pathological characteristics of the various pathology-defined subtypes.

PDF file - 57K, Quality control profiles of the samples.

Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology.

PDF file - 104K, Ability of the HER2-E subtype to predict pCR in 91 patients with clinically HER2-positive disease treated with trastuzumab-based chemotherapy in the ISPY-1, MDACC and XeNA studies.

PDF file - 104K, Association of the PAM50 Proliferation, RORS and RORP continuous scores with response and event-free survival (EFS).

PDF file - 92K, Affymetrix U133A 2.0 probes used for in this study for PAM50 subtyping.

9592 Background: We describe contemporary clinical patterns of guideline-mandated genomic testing in newly diagnosed US pts with aNSCLC. Methods: From the Flatiron Health electronic health record-derived de-identified database, we included pts with newly diagnosed advanced non-squamous cell carcinoma of the lung between 1.1.2018–6.30.2019 who had received first-line (1L) therapy. We defined inadequate testing as no successful test for at least one of four examined genes: ALK, BRAF, EGFR, and ROS1. We grouped pts according to testing received into users of next-generation sequencing (NGS) testing, including a subgroup using comprehensive genomic profiling (CGP, exemplified by Foundation Medicine, Inc.), users of non-NGS testing, and no testing. We describe the following aspects of genomic testing before the start of 1L therapy: occurrence of testing, patterns of use of testing technologies, occurrence of inadequate testing, test failures, percentage of pts with potentially missed targeted therapy with US Food and Drug Administration approval (no positive test and <4 successful tests), and recent trends in genomic testing. Results: Among 2971 included pts, 690 (23.2%) had no genomic testing before 1L treatment. Among pts who had a test (n=2281), 59.4% (n=1355) received NGS (CGP: 18.8%, n=429), while 40.6% (n=926) received non-NGS tests only. In the CGP user group, 79.7% of pts received no other type of test, compared with 29.8% of pts in the other NGS group. Inadequate testing was recorded in 13.4% of NGS-tested pts (CGP: 4.9%), compared with 52.5% of pts tested by non-NGS only. Test failures contributed to unsuccessful testing in 4.2% of pts tested by NGS (CGP: 1.2%) and in 6.8% of pts who received non-NGS tests. In the NGS group, 10.1% (CGP: 3.0%) of patients potentially missed a targeted therapy option, compared with 40.3% in the non-NGS group. EGFR and ALK testing were performed in ≥95% of pts, regardless of the testing group; however, only 83.6% and 55.7% of pts received tests for ROS1 and BRAF, respectively, in the non-NGS group. In the latter group, for the first 6 months of 2019, 88.4% and 58.2% of pts were tested for ROS1 and BRAF mutations, respectively. Conclusions: Not performing any, or performing only inadequate genomic testing in pts with newly diagnosed aNSCLC remains a concern in clinical practice. The use of NGS, particularly CGP, may help to avoid suboptimal testing, minimize test failures, and improve uptake of testing for newly introduced biomarkers, enabling individualized, targeted therapy.

Knowledge of contemporary patterns of cancer-of-unknown-primary-origin (CUP) diagnostic work-up, treatment, and outcomes in routine healthcare is limited. Thus, we examined data from elderly patients diagnosed with CUP in real-world US clinical practice. From the Surveillance, Epidemiology, and End Results–Medicare-linked database, we included patients ≥ 66 years old with CUP diagnosed between 1 January 2013 and 31 December 2015. We analyzed baseline demographics, clinical characteristics, methods of diagnostic work-up (biopsy, immunohistochemistry, imaging), treatment-related factors, and survival. CUP diagnosis was histologically confirmed in 2813/4562 patients (61.7%). Overall, 621/4562 (13.6%) patients received anticancer pharmacotherapy; among these, 97.3% had a histologically confirmed tumor and 83.1% received all three procedures. Among those with a histologically confirmed tumor, increasing age, increasing comorbidity score, not receiving all three diagnostic measures, and having a not-further specified histologic finding of only ‘malignant neoplasm’ were all negatively associated with receipt of anticancer pharmacotherapy. Median overall survival was 1.2 months for all patients. Median time between CUP diagnosis and treatment initiation was 41 days. Limited diagnostic work-up was common and most patients did not receive anticancer pharmacotherapy. The poor outcomes highlight a substantial unmet need for further research into improving diagnostic work-up and treatment effectiveness in CUP.

Next-generation sequencing (NGS) may enable more focused and highly personalized cancer treatment, with the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines now recommending NGS for daily clinical practice for several tumor types. However, NGS implementation, and therefore patient access, varies across Europe; a multi-stakeholder collaboration is needed to establish the conditions required to improve this discrepancy. In that regard, we set up European Alliance for Personalised Medicine (EAPM)-led expert panels during the first half of 2021, including key stakeholders from across 10 European countries covering medical, economic, patient, industry, and governmental expertise. We describe the outcomes of these panels in order to define and explore the necessary conditions for NGS implementation into routine clinical care to enable patient access, identify specific challenges in achieving them, and make short- and long-term recommendations. The main challenges identified relate to the demand for NGS tests (governance, clinical standardization, and awareness and education) and supply of tests (equitable reimbursement, infrastructure for conducting and validating tests, and testing access driven by evidence generation). Recommendations made to resolve each of these challenges should aid multi-stakeholder collaboration between national and European initiatives, to complement, support, and mutually reinforce efforts to improve patient care.

Background Carcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600x). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined. Results A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB >= 16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score >= 50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%. Conclusions Thirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 Implications for Practice The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.