The Targeted Pulse: An Approval for Colorectal Cancer, AI Model Enhances Palliative Care, and More


The FDA approved adagrasib with cetuximab for KRAS G12C-mutated CRC and an AI-driven mortality models improve palliative care. We also cover data on datopotamab deruxtecan showing promise in HER2-low breast cancer, zanubrutinib plus venetoclax achieving 100% ORR in high-risk CLL/SLL, and an overview of treatments HER2-targeted treatments highlighting T-DXd in CNS involvement.

Sketch of human GI tract

Adagrasib With Cetuximab Receives Approval in KRAS G12C-Mutated CRC

The FDA has approved adagrasib (Krazati) with cetuximab (Erbitux) for patients with previously treated locally advanced or metastatic colorectal cancer and who harbor a KRAS G12C mutation. Prior treatment included fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The approval is based on data from the KRYSTAL-1 study (NCT03785249), which showed promising clinical activity with a manageable safety profile.

Updated results of the phase 1/2 KRYSTAL-1 trial were presented at the 2024 American Association for Cancer Research Annual Meeting and published in Cancer Discovery. There, the overall response rates were confirmed for patients participating in both phase 1 and 2 cohorts and updated duration of response data and disease control rates were reported.

AI Mortality Model Improves Palliative Care By Predicting End-of-Life

Data from a prognostic study showed that artificial intelligence (AI) significantly outperformed oncologists in predicting short-term mortality, leading to the AI-driven mortality model at City of Hope Comprehensive Cancer Center in Duarte, California. Finly Zachariah, MD, explained the implementation of the model and how it eased clinician workload by setting up alerts for when to initiate conversations with patients regarding goals of care.Zachariah is an expert in palliative medicine and associate clinical professor in the Department of Supportive Care Medicine at City of Hope. He is also cofounder and chief medical officer of Empower Hope and lead author of the 90-day mortality model paper.

“We need to do better with effectively balancing the best we have to offer in medical care and scientific advancements with the intentional provision of adequate time for patients and their families to reflect, decide, and ensure that every aspect of the care we offer is value based, especially during critical moments, Zachariah stated. “This model helps to confirm that the last few weeks or months are most aligned to the patient’s palliative care preferences and that insight is provided to the oncologist to have those relevant conversations.”

Sketch of human breast cancer

Datopotamab Trumps Standard of Care in HER2– and HER2-Low Breast Cancer

When presented with a case regarding a woman with a history of locally advanced estrogen receptor– and progesterone receptor–positive, HER2-nonamplified disease, Timothy J. Pluard, MD, provided insights on data regarding the benefits of datopotamab deruxtecan [Dato-DXd] in the scenario. In the discussion, Pluard highlighted updates from the ongoing phase 3 TROPION-Breast01 trial (NCT05104866), which is evaluating the agent against standard-of-care chemotherapy.

“I am anxious to see how Dato-DXd data matures…. We don’t have overall survival (OS) data for this agent; that may change some people's thinking about where and how to use this if the OS data are not comparable to the other TROP2 ADCs [antibody-drug conjugates]…. We have a few ADCs to choose from moving forward, so it's going to get more complicated but there are more options for our patients.” Pluard is the medical director at Saint Luke’s Cancer Institute in Kansas City, Missouri.

Sketch of blood cancer cells

Zanubrutinib Plus Venetoclax Scores 100% ORR in High-Risk CLL/SLL

The combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) achieved a 100% overall response rate in patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma with 17p deletions and/or TP53 mutations. Results come from arm D of the phase 3 SEQUOIA trial (NCT03336333) where the combination was compared with zanubrutinib alone (arm A) or bendamustine (Bendeka) plus rituximab (Rituxan; arm B). Data were presented at the 2024 EHA Congress.

“With preliminary results for zanubrutinib plus venetoclax [in arm D of SEQUOIA], we do see a favorable safety and tolerability profile with no new [safety signals]. Rates of atrial fibrillation and hypertension were low,” study author, said Paolo Ghia, MD, PhD, IRCCS Ospedale San Raffaele and Universita Vita-Salute San Raffaele in Milan, Italy. “The study is ongoing, and hopefully in the next few years, we will be presenting results after stopping [treatment] due to undetectable MRD,” he stated.

Catching Up On HER2-Targeted T-DXd Therapy With CNS Involvement

In this article, the sequencing of HER2-targeted therapies is explored, bringing clinicians up to speed on the quickly evolving landscape. Various findings are highlighted, including data from the phase 3 EMILIA trial (NCT00829166) and the phase 3 DESTINY-Breast03 trial (NCT03529110), which evaluated trastuzumab deruxtecan (T-DXd; Enhertu) compared with T-DM1. Other trials include DESTINY-Breast-01 (DB-01; NCT03248492), -02 (DB-02; NCT03523585), and -03 (DB-03; NCT03529110). Sara Hurvitz, MD, senior vice president, director, and professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington, comments on these data and the changing landscape moving forward.

“These responses are challenging our paradigm thinking that bulky ADCs cannot get past the blood-brain barrier and impact cancer in the brain,” Hurvitz said. “Clearly, there are benefits seen in multiple trials of ADCs, and we need a better understanding of whether we can be sequencing ADCs after ADCs. This is a rapidly evolving field. We need our patients to enroll in clinical trials and help be part of the acquisition of new knowledge to help guide our treatment in the future,” she concluded.

Thank you for joining us for this week’s Targeted Pulse. Look out for more recaps to come.

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