Standard of care in unfavorable cancer of unknown primary (CUP) typically comprises platinum-based doublet chemotherapy as first-line treatment, which leads to a median overall survival (OS) of 9–12 months [1]. Several trials have investigated site-specific treatment based on tissue of origin prediction using gene expression or methylation profiling, without delivering practice-changing results [2‒4]. At the same time, large comprehensive genomic profiling (Cgp) studies detected targetable alterations in about 30% of patients with CUP [5].

Late Breaking Abstract 16: Primary Analysis of Efficacy and Safety in the CUPISCO Trial – A Randomized, Global Study of Targeted Therapy or Cancer Immunotherapy Guided by Cgp versus Platinum-Based Chemotherapy in Newly Diagnosed, Unfavorable CUP

The multicenter phase II CUPISCO trial (NCT03498521) included 636 patients with newly diagnosed, unfavorable, non-squamous CUP [6]. Following three cycles of platinum-based induction chemotherapy, patients responding to therapy (category 1) were randomized 3:1 to receive either molecularly guided therapy (MGT) based on the results of Cgp of the tumor tissue and/or liquid biopsy, or continuation of the induction chemotherapy. Patients with progressive disease after induction (category 2) could receive MGT without randomization. The trial met its primary endpoint, demonstrating a statistically significant progression-free survival (PFS) benefit in favor of MGT in category 1 patients {median PFS 6.1 months (95% confidence interval [CI] 4.7–6.5) versus 4.4 months (95% CI: 4.1–5.6), hazard ratio (HR) 0.72 (95% CI: 0.56–0.92); p = 0.0079}. Importantly, upon excluding the cohort that received combined atezolizumab and chemotherapy in the absence of targetable alterations, MGT sustained a clear PFS benefit (median MFS 8.1 months, 95% CI: 4.6–8.7) compared to both continuation of chemotherapy (median PFS 4.4 months, 95% CI: 4.1–6.3) and combined chemoimmunotherapy (median PFS 5.5 months, 95% CI: 4.5–6.4).

Although OS data are still immature, a clear trend to improvement of median OS could be observed (median OS 14.7 [95% CI: 13.3–17.3] versus 11.0 months [9.7–15.4], HR: 0.82; 95% CI: 0.62–1.09; p = 0.1779). Response rates also significantly favored MGT (overall response rate [ORR] 17.8 vs. 8.2%, ΔORR 9.6% [95% CI: 2.4–16.8], p = 0.0141), with similar duration of response in each arm (HR: 0.95; 95% CI: 0.33–2.72). Adverse event rates were generally similar in both treatment arms. No difference in quality of life was observed.

Based on these data, the CUPISCO trial demonstrated the value of including Cgp in the initial diagnostic work up to inform treatment decisions in patients with CUP. Using tissue and liquid biopsies led to more treatment options, making CUPISCO the first randomized CUP trial to demonstrate a survival improvement in the frontline setting after decades of intensive research, potentially leading to novel treatment options in this patient population. In this light, it is important to consider that CUPISCO is the first randomized trial in precision oncology yielding positive results.

Additional important questions remain regarding universal access to broad genomic profiling and innovative treatment options. Following compelling evidence in favor of molecular diagnostics and targeted treatments in several cancer types, implementing these procedures into the clinical practice constitutes a major challenge in the era of precision medicine. As biomarker-driven drugs are no longer limited to very few patients, but rather increasingly represent the standard of cancer care, health systems worldwide face growing challenges regarding the sustainability of equitable health care, making fundamental changes to help address such challenges essential.

Late Breaking Abstract 100: CUP-ONE Trial – A Prospective Double-Blind Validation of Molecular Classifiers in the Diagnosis of Cancer of Unknown Primary and Clinical Outcomes

The CUP-ONE trial (ISRCTN17282276, EudraCT: 2008-000657-35) prospectively compared tissue of origin prediction using gene expression profiling based on a 92-gene assay (CancerTYPE ID, CTID) versus centralized immunohistochemistry (C-IHC) with 10 markers [7]. Six hundred forty one patients were classified using histological and clinical data as a reference diagnosis (RD). Available tissue samples were double-blindly randomized to tissue of origin classification using either C-IHC (n = 329) or CTID (n = 418). Investigators were expected to classify each sample as one of 14 cancer types or as indeterminate. Primary endpoint was the proportion of matched samples by a classifier to the reference diagnosis site of origin in the intention to diagnose population (n = 392) with patients that had at least one available classifier output. Among the 641 patients included in the study, 118 were classified to have a known primary site, while 75 had a suspected and 451 an unknown primary (i.e., CUP). In the intention to diagnose population, sample inadequacy led to 306 C-IHC and 362 CTID classifications. Pairwise comparisons of the two classifiers revealed correct classification in 50.6% of cases using CTID and 33.3% of cases using C-IHC (difference 17.2%, 95% CI: 1.9–29.6%, p = 0.0243). Agreement of two classifiers occurred in 97% of cases. Subgroup analysis revealed that both classifiers identified lung, colorectal, breast, and ovary well, but CTID did particularly well with cholangiocarcinoma/gallbladder (60% accuracy) but not with pancreas (9.1%) versus C-HIC (27.2%). Median OS was poor across all groups: CUP 5.3 months, 95% CI: 4.6–6.4; suspected primary 9.0 months, 95% CI: 8.3–11.9; confirmed primary site 7.8 months, 95% CI: 5–13. Overall, the CTID classifier showed similar performance as C-IHC and performed better in the difficult to diagnose subgroups of cholangiocarcinoma and gallbladder cancer, producing a clinically meaningful outcome in this subset.

Abstract 1208MO – A Randomized Phase III Trial of Site-Specific Therapy Guided by the 90-Gene Expression Assay ORIGIN-PanCAoR versus Empiric Chemotherapy in Patients with Cancer of Unknown Primary

In this randomized phase III trial (NCT03278600), patients with newly diagnosed CUP not amenable to local ablative treatment were randomized 1:1 to receive either empiric chemotherapy or site-specific treatment following tissue of origin prediction based on the ORIGIN-PanCA○R 90-gene expression assay [8]. Site-specific treatments were administered according to the current standards for the respective entity. The primary endpoint was PFS in the intention-to-treat population. One hundred and eighty-two patients were randomly assigned to receive site-specific (n = 91) or empiric chemotherapy (n = 91). Site-specific therapy resulted in more treatment options than the control arm. At a median follow-up of 42.9 months, the median PFS was significantly longer with site-specific therapy than with empiric chemotherapy (9.6 vs. 6.6 months; HR: 0.68; 95% CI: 0.49–0.93; p = 0.017), while a trend for favorable OS was observed with site-specific therapy compared with empiric chemotherapy (28.2 vs. 19.0 months) in the intention-to-treat population. Frequency of adverse events (AEs) of grade ≥3 was similar between the two groups (p = 0.61).

In conclusion, site-specific treatment guided by the ORIGIN-PanCAoR assay resulted in improved PFS compared to empirical chemotherapy in this cohort of newly diagnosed CUP. More mature results including detailed characterization of the trial population and the administered treatment regimens would help clarify the implications for the clinical practice and identify the patients that could potentially benefit from this approach.

Taken together, the trials presented at ESMO 2023 pave the way for the use of Cgp as a critical component of the diagnostic workup in CUP. The use of molecularly guided therapies significantly improved the outcomes of patients with newly diagnosed CUP, potentially replacing empirical chemotherapy, which has been the standard of care for generations. Regarding patients without any targetable alterations, gene expression profiling could help identify the site of origin in particularly challenging cases, such as cholangiocarcinoma or gallbladder cancer, allowing for site-specific treatment.

RAS mutations are among the most common drivers of oncogenesis, accounting for a significant proportion of human cancers [9]. With the advent of treatment options in KRASG12C mutant cancers, the spell of being “undruggable” has been lifted and novel compounds targeting mutant KRAS are at different stages of clinical development. At ESMO 2023, data on RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor, has been presented. RMC-6236 uses its tri-complex inhibition strategy to target three major RAS isoforms: KRAS, HRAS, and NRAS. This approach might help address the genetic heterogeneity of RAS mutations observed in different malignancies: by simultaneously targeting multiple RAS isoforms, RMC-6236 effectively inhibits the downstream signaling cascade of RAS, disrupting key pathways responsible for tumor cell survival and proliferation.

Abstract 652O – Preliminary Clinical Activity of RMC-6236, a First-in-Class, RAS-Selective, Tri-Complex RAS-MULTI(on) Inhibitor in Patients with KRAS Mutant Pancreatic Ductal Adenocarcinoma, and Non-Small Cell Lung Cancer

Kathryn Arbour et al. presented preliminary data of 111 patients, consisting of 46 patients with KRAS-mutated non-small cell lung cancer (NSCLC) and 65 patients with pancreatic ductal adenocarcinoma (PDAC), who were treated with RMC-6236 [10]. All patients had previously received their respective standard of care.

The majority of patients harbored KRASG12D mutations (NSCLC 44%; PDAC 49%), closely followed by KRASG12V mutations (NSCLC 41%; PDAC 29%). The group of pancreatic cancer patients also included some cases with mutations in KRASG12R (20%). Notably, patients with KRASG12C mutations were excluded from the study.

Median age of patients was 65 years for NSCLC and 64 years for PDAC. RMC-6236 was administered once daily in a 21-day cycle. Basic efficacy in terms of tumor regression was demonstrated at doses of 80–120 mg. Dose-limiting toxicities occurred at a dose of 220 mg. Therefore, a dose of 200 mg was selected for further investigation. Common adverse reactions during treatment were rash (81%), nausea (46%), vomiting (33%), diarrhea (39%), stomatitis (22%), and fatigue (15%). In rare cases, there was a mild increase in transaminases. QT prolongation has also been reported in rare cases. Overall, reported AEs were mostly lower grade. Dose reductions were required in 14% of patients due to AEs, and treatment was discontinued in 1% of patients due to AEs.

Overall, the mean duration of treatment at the time of data analysis was 2.1 months (95% CI: 0.2–10.9). In the group of NSCLC patients, a first efficacy analysis was performed in 40 patients treated with RMC-6236 for at least 8 weeks. The ORR was 38% (n = 15), including 3 cases with unconfirmed PR according to RECIST 1.1. The disease control rate (DCR), i.e., all patients with CR/PR/SD, was 85% (n = 34). Median time to response was 1.4 months (95% CI: 1.2–2.7) and the median duration of treatment was 3.1 months (0.5–10.9).

While the ORR in patients with PDAC was reported as 20% (n = 9), central confirmation in a significant proportion of patients was pending. The DCR was 87% (n = 40). Overall, SD (67%, n = 31) or PR was documented in most cases (20%, n = 9). Median time to response and median duration of treatment were not reported for this subgroup.

In 23 patients, KRAS variant allele frequency (VAF) was also determined by measuring ctDNA before and during treatment with RMC-6236. Eighty percent of NSCLC patients and 92% of PDAC patients showed a >50% reduction in KRAS mutant alleles.

There appears to be a potential correlation between the reduction in KRAS VAF, as determined by comparing ctDNA levels, and clinical response to therapy. Thus, the overall reduction in KRAS VAF was lower in NSCLC patients and in PDAC patients with PD compared to patients with PR or SD

In conclusion, RMC-6236 is the first in a new class of RAS-selective tri-complex RAS-MULTI(ON) inhibitors. These first data demonstrate preliminary signs of efficacy in patients with previously treated NSCLC and PDAC with manageable toxicity. To assess long-term safety and clinical efficacy, longer follow-up and larger case numbers are needed. Furthermore, as patients rapidly progressed on monotherapy, combination with other targeted agents or cytotoxic chemotherapy might be important next steps in the development of the compound toward clinical utility. In the future, the use of ctDNA monitoring might provide an additional useful tool for efficacy monitoring.

Apart from the promising results from the RAS inhibitors and the CUPISCO trial, encouraging results of fibroblast growth factor receptor (FGFR) inhibitors in metastatic pancreatic cancer have been shown at ESMO 2023. Metastatic pancreatic cancer is known for its dismal prognosis and poor systemic treatment options. Testing for genetic mutations could be useful for targeted therapy.

FGFR alteration can affect the carcinogenesis in many cancer entities including, e.g. cholangiocarcinoma, pancreatic cancer, breast cancer, and urothelial cancer [11]. The four known FGFR receptors 1–4 can have different alterations, including gene fusions, copy number alterations, and single-nucleotide variants [12]. Erdafitinib is an approved oral selective pan-FGFR tyrosine kinase inhibitor for the treatment of locally advanced or metastatic urothelial carcinoma in adults with FGFR3/2 alterations who have progressed after at least one line of platinum-based chemotherapy [13].

Abstract 1621P: Efficacy and Safety of Erdafitinib in Adults with Pancreatic Cancer and Prespecified Fibroblast Growth Factor Receptor Alterations in the Phase II Open-Label – Single-Arm RAGNAR Trial

The RAGNAR study, conducted by Pant et al. [14] aimed to investigate the efficacy and safety of Erdafitinib in adult patients with pancreatic cancer. In this open-label, single-arm phase 2 study, patients with advanced pancreatic cancer were included that had progressed after at least one systemic therapy. This report presents the results of 18 patients with pancreatic cancer treated with Erdafitinib in the RAGNAR study. The primary endpoint of this study was ORR, while secondary endpoints were duration of response, DCR, and PFS.

As of the data cutoff on August 15, 2022 (median survival follow-up of 15.24 months), 18 patients with pancreatic cancer received Erdafitinib. Seventeen patients (94.4%) had visceral metastases, and there was a median of 3 previous systemic therapies (ranging from 1 to 9); 1 patient (5.6%) responded to the last therapy. Importantly, all patients had FGFR fusions (14 FGFR2 and 4 FGFR1), with no FGFR mutations detected. In this setting, none of the patients had KRAS co-alterations, and no known KRAS gatekeeper mutations were found. These results highlight the importance to diagnose the small subgroup of KRAS-wildtype pancreatic cancer patients, as they often harbor targetable (MAPK-pathway) alterations [15].

At a median follow-up time of 13.83 months, ORR was 55.6% (95% CI, 30.8–78.5%) with a substantial reduction in tumor lesions. This represented the second-highest ORR among observed responses in 16 different tumor types. The median time to response was 1.45 months. Responses were observed in patients with FGFR1 and FGFR2 fusions.

The most common AEs included dry mouth, diarrhea, stomatitis, dry skin, hyperphosphatemia, and fatigue. Five patients (28%) experienced serious AEs, and 2 patients (11%) discontinued Erdafitinib due to AEs. No treatment-related deaths were observed.

Overall, this study suggests that Erdafitinib holds promise as a treatment option for patients with KRAS-wildtype pancreatic cancer who harbor FGFR fusions or rearrangements and have exhausted standard therapies. The results of this study are encouraging for the development of new drugs in the treatment landscape of pancreatic cancer. Further translational research is needed to underline these results and stimulate genetic testing in pancreatic cancer.

M.P. was supported by the Clinician Scientist Program of the Faculty of Medicine, University of Heidelberg. M.P. and M.K. were supported by an ESMO congress scholarship by the “Working Group Medical Oncology within German Cancer Society (AIO),” including donations from Amgen, Takeda Pharma, and AstraZeneca. The Translational Oncology Working Group of the AIO congress scholarship program sponsored three young physicians to attend the ESMO in Madrid in 2023. The aim of the program was to enable young doctors and medical doctoral students to attend congresses and exchange ideas with expert mentors. The scholarship recipients co-authored this manuscript. We acknowledge the German AIO translational oncology steering board (“Leitgruppe Translationale Onkologie”) for their support. The 2024 AIO Translational Oncology Scholarship will sponsor junior physicians to attend ESMO 2024 in Barcelona. For information on next year’s scholarships and the application process for junior physicians, see the AIO website: https://www.aio-portal.de/.

M.P., M.K., and L.E.R.: none. A.B.: travel, accommodation, and expenses: Amgen. A.H.S.A.: travel reimbursement: Nordic, Servier, Merck KgaA, MSD, Pfizer, Pierre-Fabre, Roche, AMGEN. Honoria by MSD, Servier, Merck KgaA, MSD, Pfizer, Pierre-Fabre, Roche, AMGEN, and BMS. A.Bl. has received honoraria/speakers’ fees or served on advisory boards for Bayer, BMS, Takeda, MSD, Boehringer, AstraZeneca, Sanofi, Pfizer, Lilly, Amgen, Roche, Novartis, Janssen, Daiichi, Mirati, Servier, Merck, Pierre-Fabre, Merck; serves as an officer for the “Working Group Medical Oncology within German Cancer Society (AIO)” and DGHO. C.B.W. has received honoraria/speakers” fees from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX, Taiho; served on advisory boards for Amgen, Bayer, BMS, Celgene, Incyte, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, Roche; has received travel support by Bayer, Celgene, Janssen, RedHill, Roche, Servier, Taiho; and has received research grants (institutional) by Roche. Serves as an officer for the European Society of Medical Oncology (ESMO) and “Working Group Medical Oncology within German Cancer Society (AIO)” and on expert committees for the German Cancer Aid (Deutsche Krebshilfe) and German Cancer Society (Deutsche Krebsgesellschaft) is a member of the EU Commission expert group: Mission Board for cancer.

The AIO ESMO congress scholarship 2023 was funded by an unrestricted grant by donations from Amgen, Takeda Pharma, and AstraZeneca.

Maria Pouyiourou, Lea E. Reitnauer, Alexej Ballhausen, Annalen Bleckmann, C. Benedikt Westphalen, Annabel H.S. Alig, and Maximilian Kloft played a substantial role in conceptualizing the article, drafting the manuscript, critically revising it, providing final approval for the published version, and confirming their commitment to being accountable for all aspects of the work.

Additional Information

Maria Pouyiourou, Lea Elisabeth Reitnauer, and Alexej Ballhausen contributed equally to this work.

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