Barcelona, September 18, 2021. Featuring among our pre-selection of VHIO research highlights (1) at this week’s virtual 2021 annual Congress of the European Society for Medical Oncology (ESMO), 18-21 September, we flagged up several studies aimed at advancing precision medicine in colorectal cancer. Selected to showcase as either oral presentations or ePosters, the following research has now been presented, discussed and debated throughout the course of this meeting:
DESTINY-CRCO1: exploratory biomarker analysis in tumor & liquid biopsy
Results previously reported at the American Society of Clinical Oncology (ASCO) Virtual Annual Meeting, 04 – 08 June, from the phase II, multicenter, open-label DESTINY-CRC01 trial showed that treatment with an antibody-drug conjugate (ADC), trastuzumab deruxtecan-nxki, produced durable responses in patients with previously treated HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trials assessing this therapy.
DESTINY-CRC01 Investigators, including Elena Élez, Medical Oncologist and Clinical Investigator of VHIO’s Gastrointestinal and Endocrine Tumors Group, subsequently performed exploratory biomarker analysis in tumor and liquid biopsy to seek out potential mechanisms of resistance and response towards more precisely matching patients to this particular treatment.
The results of this latest research (2), were presented by lead author Salvatore Siena, Università degli Studi di Milano (Milan, Italy) during the Proffered Paper session – Gastrointestinal tumours, colorectal 1. Biomarker data in paired ctDNA samples collected at baseline and disease progression from 30 patients with HER2-positive metastatic colorectal cancer, indicate that antitumor activity correlates with baseline HER2 expression or amplification in both tumor and liquid biopsy.
“In our quest to develop more effective therapies and improve outcomes for our patients, we must continue to advance insights into the mechanisms underlying resistance to treatment and to evaluate response to novel therapies by robust biomarker analysis,” observed co-author Elena Élez, who is also coordinator of colorectal cancer research at VHIO, headed by VHIO’s Director, Josep Tabernero.
She continued, “This compound has shown promising activity in metastatic colorectal cancer without RAS/BRAF mutation and with HER2 overexpression. While this is a highly selected population, this antibody-drug conjugate might provide a much needed, alternative treatment option for these patients.”
In paired ctDNA samples by liquid biopsy that were collected at the beginning of the study and during disease progression, acquired alterations were observed in several genes, but none were common across patients. She concluded, “Further studies assessing the potential mechanisms of resistance to and patient selection for this therapy in patients with HER2-positive metastatic colorectal cancer are warranted.”
Molecular tumor profiling & matched molecular targeted treatment of YOCR
Mentored by Elena Élez, Iosune Baraibar, a Clinical Investigator of VHIO’s Gastrointestinal and Endocrine Tumors Group, presented a study on molecular tumor profiling and matched molecular targeted treatment towards the more effective treatment of metastatic young-onset colorectal cancer (YOCR). YOCR is defined as diagnosis under the age of fifty years old. Over the past decades, the incidence of colorectal cancer in young adults has increased at an alarming rate, but causes and pathogenesis still remain unknown.
“While the early detection of colorectal cancer has demonstrated to improve survival rates, adults under fifty are not yet included in screening programs and YOCR is not well characterized,” said Iosune Baraibar, who is also a Medical Oncologist at the Vall d’Hebron University Hospital’s Medical Oncology Department, led by VHIO’s Director, Josep Tabernero.
In response, the investigators aimed to characterize the molecular characteristics of over 100 patients with metastatic YOCR who had molecular tumor profiling data, and assess the impact of tumor genomic profiling on improving outcomes for these patients. Considering that YOCR is generally diagnosed at a more advanced stage than standard-onset colorectal cancer, with a poorer course of the disease, this represents an unmet clinical need.
Selected by ESMO as an ePoster (3) results showed that these patients do not present molecular alterations in current screening programs, which hinders their enrollment in phase I trials with therapies that hone in on specific molecular targets. “Our findings also suggest that these patients significantly benefit from immune-based therapies, although the intrinsic mechanisms behind of this noted response should be further investigated,” added Iosune Baraibar. “As importantly, this study represents a call for action in colorectal cancer. Results support the unmet need of initiating screening programs in adults younger than 50 years,” she concluded.
Clinical prognostic characteristics: a stratification tool for refractory colorectal cancer patients?
Under the supervision of Medical Oncologist and Clinical Investigator, Francesc Salvà, and co-authored by other researchers of VHIO’s Gastrointestinal and Endocrine Tumors Group, as well as other teams, Augusto A. Valdivia presented an ePoster (4) on the role of clinical prognostic characteristics as a potential stratification tool to more effectively determine which patients with refractory metastatic colorectal cancer (refMCRC) would benefit from late-line therapies.
“We aimed to establish the potential utility of strategy in routine clinical practice or clinical trials. To do so, we assessed the function of prognostic factors in 735 patients with refractory metastatic colorectal cancer who were attended at our hospital, the Vall d’Hebron University Hospital, from 2010 to 2020,” said Francesc Salvà.
Supporting previously reported data, a correlation was observed between these prognostic characteristics, based on tumor burden, distribution of metastatic disease and the time of disease evolution of advanced colorectal cancer, and the prognosis of these patients. “The strength of this study lies in the large number of patients analyzed who were treated during routine clinical practice. Furthermore, according to our findings, more than one third of these refractory patients treated at Vall d’Hebron, received a third-line therapy and more than half were included in clinical trials with longer median overall survival compared to previous data,” concluded Francesc Salvà.
Prognostic & predictive factors in BRAF-V600E mutated colorectal cancer
Francisco Javier Ros, Medical Oncologist and Clinical Investigator of the same group, presented an ePoster (5) on prognostic factors in BRAF-V600E mutated colorectal patients treated with BRAF inhibitor+antiEGFR +/- MEK inhibitor. BRAF-V600E mutated metastatic colorectal cancer is an aggressive disease with poor overall survival under standard chemotherapy.
Various studies reported in the literature have shown how treatment with doublet and triplet targeted combinations, such as BRAF inhibitor+antiEGFR +/- MEK inhibitor, improve outcomes for these patients. While prognostic factors in this patient population have previously been described, this is not the case in a homogeneous population treated with BRAF inhibitor-based therapy.
In response, the investigators assessed the data of an international cohort of patients who received doublet or triplet anti-BRAF combinations in clinical trials or as compassionate use. They found that patients’ characteristics including the number of metastatic sites and carcinoembryonic antigen levels, are important determinants of overall survival for this patient population.
“Our study suggests that these prognostic factors could help in clinical practice and may also be considered as stratification factors in future clinical trials,” said Francisco Javier Ros.
- VHIO News: https://www.vhio.net/esmos-2021-virtual-congress-16-21-september-a-pick-of-vhio-research-highlights/.
- 386O – Exploratory biomarker analysis of DESTINY-CRC01, a phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd, DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC).
- Baraibar Argota, J. Ros, R. Comas, S. Aguilar, F. Salva, A. Garcia, J.L. Cuadra Urteaga, N. Saoudi Gonzalez, N. Mulet Margalef, J. Hernando, J. Capdevila, M. Martí, E. Espín, E. Garralda, P. Nuciforo, R. Dienstmann, A. Vivancos, J. Tabernero, M.E. Elez Fernandez. 461P – Molecular tumor profiling and matched molecular targeted treatment in metastatic young-onset colorectal cancer (YOCR). Ann. Oncol. (2021) 32 (suppl_5): S530-S582. 10.1016/annonc/annonc698.
- A. Valdivia, F. Salva, J. Ros, I. Baraibar, G. Argiles Martinez, N. Saoudi Gonzalez, A. Garcia, N. Mulet Margalef, J.L. Cuadra Urteaga, J. Capdevila, M.A. Salud Salvia, D. Paez, E. Casado, R. Comas, F. Ruiz-Pace, G. Villacampa Javierre, D.A. Acosta Eyzaguirre, R. Dienstmann, M.E. Elez Fernandez, J. Tabernero. 426P – Spotlight on refractory metastatic colorectal cancer (refMCRC): Role of prognostic characteristics in the continuum of care. Ann. of Oncol. (2021) 32 (suppl_5): S530-S582. 10.1016/annonc/annonc698.
- J. Ros Montana, G. Martini, G. Villacampa Javierre, I. Baraibar, R. Comas, A. Garcia, F. Salva, N. Saoudi Gonzalez, D. Ciardiello, R.D.A. Toledo, E. Martinelli, F. Ciardiello, A. Vivancos, H.G. Palmer, R. Dienstmann, J. Tabernero, M.E. Elez Fernandez. 445P – Tumor load surrogates as major prognostic factors in BRAF-V600E mutated (mt) colorectal (CRC) patients treated with BRAF inhibitor+antiEGFR +/- MEK inhibitor. Ann. Oncol. (2021) 32 (suppl_5): S530-S582. 10.1016/annonc/annonc698.