Katrina S. Pedersen, MD, MS, discusses key updates in the therapeutic landscape for patients with molecularly targetable metastatic colorectal cancer.

Dr Pederson on Novel Therapies for the Management of Targetable mCRC

Katrina S. Pedersen, MD, MS, associate professor, John T. Milliken Department of Medicine, Division of Oncology, Medical Oncology program leader, cofounder, Young Onset Colorectal Cancer Program, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discusses key updates in the therapeutic landscape, highlighting emerging therapies for patients with molecularly targetable metastatic colorectal cancer (mCRC).

In 2023, notable advancements in the mCRC space included the FDA approval of the HER2 inhibitor 

tucatinib (Tukysa) in combination with trastuzumab (Herceptin)

 for patients with mCRC who have progressed after standard frontline and second-line chemotherapy, Pedersen begins. This approval marked the first FDA-approved anti-HER2 therapy for mCRC, providing new treatment options for this molecularly targeted subset of patients, she explains.

Another noteworthy development is the emergence of adagrasib (Krazati) in 

 G12C-mutated disease, Pedersen continues. Trials investigating adagrasib demonstrated durable and meaningful benefits, particularly when combined with an estrogen receptor inhibitor like panitumumab (Vectibix), she states. For example, administration of adagrasib plus cetuximab (Erbitux) was well tolerated and demonstrated clinical activity in the multicohort phase 1b/2 KRYSTAL-1 study (NCT03785249) of patients with previously treated KRAS G12C-mutant locally advanced or mCRC. These data supported the acceptance of a supplemental new drug application for the combination for 

 in February 2024. This experience parallels findings with other MAP kinase-targeted interventions such as BRAF inhibitors, which are currently under FDA review and show promise for future accessibility, Pedersen adds.

Data from the phase 2 SEAMARK trial (NCT05217446), focusing on patients with BRAF V600E mutations and concurrent microsatellite instability or DNA mismatch repair deficiency, are also highly anticipated, Pedersen notes. This trial aims to evaluate the efficacy of combining BRAF-targeted therapy, such as encorafenib (Braftovi), with immunotherapy in this selected patient population, she details. The rationale behind this approach is to explore potential synergies between BRAF inhibition and immune checkpoint blockade, leveraging the unique molecular characteristics of these tumors, Pedersen concludes.

Videos

Katrina S. Pedersen, MD, MS, discusses key updates in the therapeutic landscape for patients with molecularly targetable metastatic colorectal cancer.
 

Dr Pedersen on the Evolution of Immunotherapy in HCC

Katrina S. Pedersen, MD, MS, associate professor, Department of Medicine, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine, Siteman Cancer Center, 

discusses the evolution of the role ofimmunotherapy

 in the treatment of patients with hepatocellular carcinoma (HCC).

The integration of immunotherapy into the management of HCC marks a significant milestone, substantially altering the potential clinical outcomes for patients with unresectable HCC, Pedersen begins. Notably, 2 pivotal phase 3 trials have emerged, each contributing crucial insights into the efficacy of immunotherapeutic approaches, she explains. The IMbrave150 trial (NCT03434379) investigated the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) in patients with treatment-naive systemic HCC. The HIMALAYA trial (NCT03298451), explored the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen, involving durvalumab (Imfinzi) with a priming dose of tremelimumab (Imjudo) followed by durvalumab maintenance therapy, Pedersen emphasizes.

Real-world observations with the IMbrave150 and STRIDE regimens indicate that although their real-world clinical benefits may not uniformly mirror those reported in trials, a discernible shift in the tolerability, progression-free survival (PFS), and overall survival (OS) outcomes among North American patients with HCC is evident since the introduction of these treatment options, she expands. Notably, comparative analyses between immunotherapy combinations and those incorporating VEGF-targeting agents, such as bevacizumab, have not yet been conducted, necessitating a deeper understanding of the optimal treatment strategies for patients with HCC, Pedersen states.

Clinical decision-making regarding agent selection leans heavily on individual patient profiles and clinical parameters, Pedersen continues. Nonetheless, tangible real-world benefits have been observed with both regimens, underscoring the promise of these advancements, she reports. Furthermore, the ongoing evolution of treatment approaches extends beyond mere drug combinations, delving into the integration of immunotherapy with diverse liver-directed therapies, Pedersen notes, adding that this interdisciplinary treatment approach encompasses modalities such as transarterial chemoembolization, various ablations, external beam radiation, and in select cases, resection.

As the field progresses toward next-generation combinations, the convergence of targeted therapies with immunomodulation heralds a promising era in HCC management, emphasizing the importance of interdisciplinary collaboration and personalized medicine in optimizing patient outcomes, Pedersen concludes.

 Katrina S. Pedersen, MD, MS, discusses the evolution of the role of immunotherapy in the treatment of patients with hepatocellular carcinoma.

Dr Pedersen on the Evolving Use of Cytoreductive Surgery for Peritoneal Carcinomatosis

Katrina S. Pedersen, MD, MS, associate professor, Division of Oncology, Washington University School of Medicine, discusses the evolving use of cytoreductive surgery for patients with peritoneal carcinomatosis in gastrointestinal (GI) malignancies.

There are ongoing efforts taking place aiming to standardize treatment with cytoreductive surgery across GI malignancies, particularly in the context of peritoneal carcinomatosis, Pedersen begins. Continued refinement of these approaches and an acceleration in research maylead to more conclusive trials elucidating the benefits of cytoreduction and other intraperitoneal treatments, Pedersen explains. These approaches include hyperthermic intraperitoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy, which involves the delivery of chemotherapy or other medical treatments directly into the abdominal cavity, she details.

Despite the longstanding existence of cytoreduction with or without HIPEC, the utility of this approach remains limited and difficult to access, Pedersen notes. This is because the surgeries require highly specialized surgeons to perform, have a prolonged duration, and are only performed at a limited number of centers, Pedersen explains. However, recent trials, such as the large, phase 3 PRODIGE 7 trial (NCT00769405) in France have shown that patients undergoing cytoreduction experienced significantly greater survival rates compared with those receiving systemic therapy alone, Pedersen reports, adding that this underscores the potential of cytoreductive surgery in patients with GI malignancies, she adds.

As research accelerates in this field, there is optimism that large data-driven advancements will provide a clearer understanding of the patient populations that would benefit most from cytoreductive treatments, Pedersen says. Moving forward, continued support and investment in research are crucial to better understand the optimal candidates for cytoreductive treatment, Pedersen says. By leveraging the insights gained from ongoing studies and refining patient selection criteria, the goal is to maximize the benefits of cytoreductive surgery and intraperitoneal therapies for patients with peritoneal carcinomatosis, she concludes.

Katrina S. Pedersen, MD, MS, discusses the evolving use of cytoreductive surgery for patients with peritoneal carcinomatosis.

Dr Pedersen on Updates in mCRC Management

Katrina S. Pedersen, MD, MS, associate professor, John T. Milliken Department of Medicine, Division of Oncology, Medical Oncology program leader, cofounder, Young Onset Colorectal Cancer Program, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discusses key updates and FDA approvals from 2023 for the treatment of patients with metastatic colorectal cancer (mCRC).

Patients with mCRC often receive fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, followed by a VEGF inhibitor if it is not contraindicated and an EGFR inhibitor when appropriate, Pedersen says. Historically, patients with refractory mCRC who have received 3 or more prior lines of therapy have had unmet needs, which 2 2023 FDA approvals helped address, Pedersen explains.

The phase 3 SUNLIGHT trial (NCT04737187) evaluated trifluridine-tipiracil (Lonsurf) with or without bevacizumab (Avastin) in patients with refractory mCRC who had received a maximum of 2 prior chemotherapy regimens. This trial demonstrated that trifluridine-tipiracil plus bevacizumab generated progression-free survival (PFS) and overall survival (OS) advantages vs trifluridine-tipiracil alone in this patient population. Pedersen notes that she has observed this clinical benefit with the use of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil alone in her own practice. In August 2023, 

the FDA approved the combination of trifluridine-tipiracil and bevacizumab

 for patients with previously treated mCRC based on the findings from SUNLIGHT.

 (Fruzaqla) for the treatment of adult patients with previously treated mCRC. Data from the phase 3 FRESCO-2 trial (NCT04322539) supported this regulatory decision and showed that fruquintinib plus best supportive care (BSC) produced PFS and OS benefits vs BSC alone in this patient population, including in patients who had previously received trifluridine-tipiracil and/or regorafenib (Stivarga).

The additions of trifluridine-tipiracil plus bevacizumab, as well as fruquintinib, to the mCRC treatment paradigm have provided a broad range of patients with potential treatment options beyond those approved for biomarker-selected populations, Pedersen concludes.

Katrina S. Pedersen, MD, MS, discusses key updates and FDA approvals from 2023 in metastatic colorectal cancer.

Katrina S. Pedersen, MD, MS

Articles

Dr Pederson on Novel Therapies for the Management of Targetable mCRC

Dr Pedersen on the Evolution of Immunotherapy in HCC

Dr Pedersen on the Evolving Use of Cytoreductive Surgery for Peritoneal Carcinomatosis

Dr Pedersen on Updates in mCRC Management