John L. Hays, MD, PhD, assistant professor, Department of Internal Medicine, The Ohio State University, member, Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center (OSUCC)–James, discusses the evolution of the treatment paradigm for patients with metastatic colorectal cancer (mCRC) who experience disease progression following standard chemotherapy regimens.

Traditionally, patients with mCRC who progressed on FOLFOX, FOLFOXIRI, or 5-fluorouracil (5-FU)–based regimens lacked effective treatment options in later lines, Hays begins. Many of these patients still exhibited acceptable fitness, but progressed on all available therapeutic options and could no longer be treated, he states. However, several recent advancements have expanded options for this patient population, including the breakthrough 

approval of tucatinib (Tukysa) and trastuzumab (Herceptin)

 for those with HER2-positive mCRC in January 2023.

Moreover, several novel treatment approaches are being evaluated for this patientpopulation including alternative methods of VEGF- and KRAS-inhibition, Hays continues.

The VEGF inhibitor fruquintinib (HMPL-013) previously received fast-track designation from the FDA in 2020 for patients with mCRC who had received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, VEGF-directed therapy, and 

 was submitted based on data from the randomized phase 3 FRESCO-2 trial (NCT04322539) for patients with refractory mCRC, Hays adds. This trial showed that fruquintinib plus best supportive care improved the median overall survival from 4.8 months with placebo to 7.4 months, meeting the trial’s primary end point.

Additionally, some patients with mCRC may benefit from the approval of KRAS inhibitors in this space, Hays says. Almost half of patients with CRC exhibit 

 mutations, which are associated with resistance to many current targeted therapies. Increasing the focus on developing agents that target other 

 mutations more commonly found in CRC through clinical trials could improve outcomes for this subgroup, Hays concludes.

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John L. Hays, MD, PhD, discusses the evolution of the treatment paradigm for patients with metastatic colorectal cancer who experience disease progression following standard chemotherapy regimens.
 

Dr Hays on the Evolution of Later-line Treatment Options in Refractory mCRC

John L. Hays, MD, PhD, assistant professor, Department of Internal Medicine, The Ohio State University, member, Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center–James, discusses the significance of the approval for tucatinib (Tukysa) and trastuzumab (Herceptin) for patients with HER2-positive metastatic colorectal cancer (mCRC).

Prior research into the treatment of patients with mCRC has revealed that a small patient subset of those with mCRC will express HER2. Within this population, patients who were heavily pretreated with standard-of-care 5-fluorouracil (5-FU)–based regimens were shown to respond well to HER2-targeted therapies, Hays begins. Several phase 2 trials have shown benefit with various combinations of small-molecule inhibitors, antibodies targeting HER2, or antibody-drug conjugates (ADCs), Hays adds. For example, the DESTINY-CRC01 trial (NCT03384940) of fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated the agent’s ability to produce durable responses in patients with HER2-positive mCRC. However, this and other trials have not yet led to approvals in this disease space.

The treatment armamentarium for these patients was recently expanded with the 

FDA accelerated approval of tucatinib in combination with trastuzumab

 in January 2023, Hays continues. This approval was based on data from the phase 2 MOUNTAINEER trial (NCT03043313), which included 84 patients with 

 wild-type, HER2-positive unresectable or metastatic disease that had progressed on treatment with fluoropyrimidine, oxaliplatin, and irinotecan, as well as an anti-vascular endothelial growth factor (VEGF) monoclonal antibody.

At a median follow-up of 20.7 months, results showed that the combination elicited an overall response rate of 38% (95% CI, 28%-49%). This consisted of 3.6% of patients who experienced a complete response, and 35% of patients who had a partial response, he reports. Moreover, the median duration of response with trastuzumab plus tucatinib was 12.4 months (95% CI, 8.5-20.5). No treatment-related deaths were reported, and 5.8% of patients discontinued treatment. Common adverse effects included diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia.

Prior to this approval, patients who progressed on standard 5-FU–based regimens had few avenues for continued treatment, Hays notes. This regimen provides another effective, tailored approach for this patient subset, he concludes. 

John L. Hays, MD, PhD, discusses the significance of the approval for tucatinib and trastuzumab for patients with HER2-expressing metastatic colorectal cancer.

Dr Hays on the Significance of the Tucatinib/Trastuzumab Approval in HER2-Positive mCRC

John L. Hays, MD, PhD, assistant professor, the Department of Internal Medicine, the Ohio State University, member, the Translational Therapeutics Program, the Ohio State University Comprehensive Cancer Center - James Cancer Hospital, discusses the evolution of treating patients with hepatocellular carcinoma (HCC).

The emergence of new therapies and positive clinical trials have expanded the treatment landscape for patients with HCC over the past decade, Hays begins. Looking back at the treatment landscape 10 years ago, there were a minimal number of drugs that were active in patients, Hays notes adding that sorafenib (Nexavar) showed some clinical benefit. However, that clinical benefit was minimal in most patients, and treatment with sorafenib was limited to patients that displayed signs of good liver function, Hays notes.

In recent years, new approvals featuring target therapy and immunotherapy combinations have provided new treatment options for patients with HCC, Hays continues. For example, the FDA approved 

the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin)

 for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy in May 2020 and 

the combination of durvalumab (Imfinzi) with tremelimumab (Imjudo)

 for the treatment of adult patients with unresectable HCC in October 2022.

With different targeted therapy and immunotherapy combinations approved, this has created an expanded treatment landscape with different choices to consider for each individual patient, Hays expands. Moreover, these combinations and new treatment options are helping patients live longer, and they have opened up treatment to patients who may have not been eligible for sorafenib, Hays says, noting that this was once a persistent question within HCC. Treatment options were available for patients in good health, but many patients with HCC are rarely in perfect health, he adds. These combinations could represent options for patients who do not have perfect liver function, and they have highlighted a major shift in the treatment landscape for patients with HCC, Hays concludes.

John L. Hays, MD, PhD, discusses the evolution of treating patients with hepatocellular carcinoma.

Dr Hays on the Evolution of the Treatment Landscape in HCC

John Hays, MD, PhD, an assistant professor in the Department of Internal Medicine, and member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center—James, discusses immunotherapy research in gynecologic cancer.

Research in gynecologic cancer is investigating the use of immunotherapy beyond checkpoint inhibitors. In hematologic cancers, tumor-infiltrating lymphocytes (TILs) and CAR T-cell therapies are being examined, but immunotherapy in solid tumors is still in its infancy, explains Hays. Currently, there are open trials with TILs in cervical cancer and CAR T cells in ovarian cancer, but the data regarding efficacy are still limited.

Immunotherapy is evolving in gynecologic cancer. Early trials investigating single-agent immunotherapy showed, according to Hays, disappointing results, though not negative. Many trials looking at immunotherapies in combination with targeted therapies or chemotherapies are ongoing. The hope is those results will improve for patients with gynecologic cancers, concludes Hays.

John Hays, MD, PhD, discusses immunotherapy research in gynecologic cancer.

Dr. Hays on Immunotherapy Research in Gynecologic Cancer

John Hays, MD, PhD, an assistant professor in the Department of Internal Medicine, and member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center—James, discusses the progression of immunotherapy in treating patients with ovarian cancer.

As PD-1, PD-L1, and CTLA-4 inhibitors were coming into the mainstream in many cancers a few years ago, there was an interest in investigating these agents in ovarian cancer, explains Hays. As single agents, the response rates ranged from 10% to 15%, which Hays says is “not bad,” but not as successful as he had hoped.

To try and increase response rates, researchers began investigating identifying patient populations that respond best to these drugs and figuring out what drugs can be added to these immunotherapies to make them work better, according to Hays. When chemotherapy is added to immunotherapy, there are better response rates in some cases, but not others. In addition to adding immunotherapy to chemotherapy in the upfront setting, immunotherapy is being explored in combination with chemotherapy or targeted therapy in the maintenance setting, in an effort to increase response rates and the number of patients who do not have disease recurrence, concludes Hays.

John Hays, MD, PhD, discusses the progression of immunotherapy in treating patients with ovarian cancer.

Dr. Hays on Immunotherapy in Ovarian Cancer Treatment

John Hays, MD, PhD, an assistant professor in the Department of Internal Medicine, and member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center—James, discusses investigational combinations of PARP inhibitors and immunotherapy in ovarian cancer.

The phase I/II TOPACIO/KEYNOTE-162 trial enrolled patients with 

 wild-type ovarian cancer to receive the combination of niraparib (Zejula) and pembrolizumab (Keytruda). The objective response rate (ORR) in the 

-mutant population was similar to treatment with a PARP inhibitor alone. However, patients without 

 mutations, and those who didn't have homologous recombination deficiencies, had a significantly higher ORR than would be expected with either agent alone. 

In the phase I/II MEDIOLA trial, patients with platinum-sensitive ovarian cancer who harbored germline 

 mutations received the combination of olaparib (Lynparza) and durvalumab (Imfinzi). The ORR with the combination was 75%, suggesting that immunotherapy could have a role even in pretreated populations, concludes Hays.

John Hays, MD, PhD, discusses investigational combinations of PARP inhibitors and immunotherapy in ovarian cancer.

Dr. Hays on Combining PARP Inhibitors With Immunotherapy in Ovarian Cancer

John Hays, MD, PhD, an assistant professor in the Department of Internal Medicine, and member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center—James, discusses the potential for PARP inhibitor combinations in patients with ovarian cancer.

There is a great desire, according to Hays, to combine PARP inhibitors with immunotherapy and chemotherapy due based on the mentality combining agents with proven efficacy might lead to even greater benefit for patients.

While combining these 3 approaches in ovarian cancer might yield exciting results, potential unexpected adverse events may also occur, warns Hays. Currently, the combinations being used in the treatment of patients with ovarian cancer have been fairly well tolerated, leaving investigators cautiously optimistic that they will continue to be as research in the field moves forward, says Hays.

Novel approaches are already being combined in ovarian cancer. For example, in the frontline setting, immunotherapy is being paired with PARP inhibitors or VEGF-targeting agents plus chemotherapy in an effort to increase overall response rates in patients, concludes Hays.

John Hays, MD, PhD, discusses the potential for PARP inhibitor combinations in patients with ovarian cancer.

John Hays, MD, PhD

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