10 Promising Therapies for Hard-to-Treat Cancers

Pictured: An illustration of a sunrise landscape with a cancer awareness ribbon/Nicole Bean for BioSpace†

September 24 is World Cancer Research Day, dedicated to supporting the research and innovations that improve outcomes for cancer patients across the globe. So far this year, the FDA has approved ten novel anticancer therapies, for breast cancer, multiple myeloma, acute myeloid leukemia and more.

Over the past three decades, advancements in innovative therapies, medical research, preventative care and early detection of cancer have led to a 33% reduction in cancer mortality, saving over 3.8 million lives, according to a recent report by the American Association for Cancer Research.

“As we learn more about tumor biology, oncogenic drivers and the genomic makeup of different patients, we are learning that there are better, more personalized ways to treat patients,” Christina Corridon, principal at ZS, told BioSpace.

Corridon anticipates that the oncology space will boom with cell therapies, especially singular products designed to impact a spectrum of blood and solid tumor cancers with personalized approaches.

“I’m really excited about the word ‘cure,’” Corridon said. “We’re seeing that being realized. It’s more and more at the forefront, and not just an aspiration.”

BioSpace looks at ten top therapeutic candidates in key cancer indications nearing regulatory review.

According to the Centers for Disease Control and Prevention, more people die from lung cancer in the U.S. than from any other type of cancer.

Merck’s Keytruda (pembrolizumab) remains a leader in this space, approved across several non-small cell lung cancer (NSCLC) subtypes. Checkpoint inhibitors like Keytruda work well for “hot” NSCLC tumors that show signs of inflammation, Corridon said.

However, the blockbuster drug has its limitations, with data from a Phase III trial indicating that it doesn’t work well for patients with metastatic nonsquamous NSCLC who have been previously treated with an epidermal growth factor-tyrosine kinase inhibitor (EFGR-TKI).

Accordingly, several companies are vying to challenge Keytruda’s dominance.

AstraZeneca’s Tagrisso

Phase III

Tagrisso (osimetinib) is a third-generation EGFR-TKI that is intended to treat patients with early-stage EGFR-mutated NSCLC after complete tumor resection.

In January, AstraZeneca reported results from the Phase III ADAURA trial showing that patients treated with Tagrisso achieved an overall survival rate of 88% after five years, with risk of death being cut in half.

Tagrisso won FDA approval in 2018 for the first-line treatment of patients with metastatic NSCLC who express specific EFGR mutations as detected by an FDA-approved test. AstraZeneca is investigating the drug in early-stage disease and in combination with chemotherapy.

Roche’s Tecentriq

Phase III

In a Phase III IPSOS trial, Tecentriq (atezolizumab), a checkpoint inhibitor, significantly improved overall survival (OS) in patients with advanced NSCLC who are unable to undergo platinum doublet chemotherapy.

Late-stage NSCLC patients treated with Tecentriq demonstrated a 24% survival rate at two years, compared to only 12% of participants treated with chemotherapy, Roche reported in July 2023.

The therapeutic is currently approved to treat NSCLC as an adjuvant treatment after surgery and platinum chemotherapy and as a combination regimen with other chemotherapeutic agents.

Although the annual rates of colon and rectum cancers have generally decreased over the past 20 years, the incidence of colorectal cancer (CRC) in young adults under the age of 50 has rapidly increased, according to the American Cancer Society.

A larger focus on screening has led to the early detection and treatment of CRC, Corridon said, but late-stage and metastasizing CRC remains difficult to treat. The success of current therapeutic strategies has been minimal, with the Mayo Clinic reporting recurrence rates up to 42% within five years following treatment. GSK and Bold Therapeutics aim to change that trajectory.

GSK’s Jemperli

Phase II

Researchers from Memorial Sloan Kettering Cancer Center (MSKCC) made headlines in June 2022, when a small study of GSK’s Jemperli (dostarlimab) showed a 100% complete response rate in 14 patients with mismatch repair-deficient (MMRd) locally advanced rectal cancer.

The anti-PD-1 checkpoint inhibitor is being investigated as a monotherapy in a Phase II study for patients with MMRd/microsatellite instability-high locally advanced rectal cancer. The FDA cleared the trial to begin after its Oncologic Drugs Advisory Committee voted 8-5 that two single-arm trials would be “sufficient to characterize the benefits and risks” in this patient population.

Jemperli is currently approved to treat dMMR endometrial cancer and dMMR recurrent or advanced solid tumors.

Bold Therapeutics’ BOLD-100

Phase II

Vancouver-based Bold Therapeutics presented data in April from a Phase II clinical trial showing that, in combination with standard-of-care chemotherapy, BOLD-100 elicited a disease control rate of 87% in 17 patients with advanced colorectal cancer.

BOLD-100 is a first-in-class ruthenium-based small molecule that causes malignant cell death by altering the unfolded protein response and inducing reactive oxygen species.

In the Phase II trial, presented at the American Association for Cancer Research (AACR) 2023 conference, patients treated with BOLD-100 in combination with chemotherapy showed a median progression-free survival rate of 4.7 months and an OS rate of 9.8 months, substantially higher than standard-of-care data.

Almost 300,000 new cases of invasive breast cancer will be diagnosed in women in 2023, according to data from the American Cancer Society.

Breast cancers represent a promising area to develop antibody-drug conjugates (ADCs), a trend that Corridon expects to see continue. “We think of ADCs as a much more targeted, personalized approach to delivering chemotherapy,” she said.

Here are two promising ADCs targeting some of breast cancer’s toughest cases.

Daiichi Sankyo and AstraZeneca’s Dato-DXd

Phase III

Just in time for World Cancer Research Day, Daiichi Sankyo and AstraZeneca reported positive topline results from the Phase III trial of their ADC, datopotamab deruxtecan (Dato-DXd), versus the investigator’s choice of chemotherapy.

Dato-DXd met the trial’s primary endpoint, showing a statistically significant and clinically meaningful improvement in 733 patients with previously treated inoperable or metastatic HR-positive, HER2-negative breast cancer. Detailed results are to be presented at an upcoming medical meeting.

BioNTech’s DB-1303

Phase III

DB-1303, being developed by BioNTech and DualityBio, is an ADC that inhibits topoisomerase-1, an enzyme involved in DNA replication. The companies are ushering the drug into a Phase III trial for patients with HER2-low, HR+ metastatic breast cancer with disease progression after endocrine therapy.

In a Phase I/Phase II trial, patients treated with DB-1303 in a Phase I/Phase II clinical trial saw an average disease control response of 88.5% with a favorable tolerability profile.

The Phase III trial will evaluate DB-1303’s efficacy and safety against chemotherapy in approximately 466 patients.

Stomach, or gastric, cancer develops slowly, mostly affecting individuals aged 65 and older, per the American Cancer Society.

Typically, stomach cancer is diagnosed in later stages after it has metastasized to other parts of the body. Corridon noted that clinical trials for aggressive cancers can be complex because symptomatic patients may not want to wait for a trial, opting for currently available treatments instead.

Despite challenges in clinical trials, companies are still working toward creating solutions for patients with metastasizing disease.

Astellas’ Zolbetuximab

Phase III

Zolbetuximab, in combination with a chemotherapy regimen, reduced the risk of disease progression or death by 31.3% in a Phase III trial of patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma (GEA).

A median OS rate of 14.39 months was recorded during the study.

Results of the Phase III GLOW study, plus positive results from Astellas’ SPOTLIGHT study, will serve as the basis for global regulatory submissions.

Leap Therapeutics’ DKN-01

Phase II

Developed by Cambridge, Mass-based Leap Therapeutics, DKN-01 is an anti-Dickkopf-1 (DKK1) antibody that reduces the expression of DKK1, which is associated with worse disease prognosis and poor response to chemotherapy in patients with gastric cancer.

In a Phase II study presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, the antibody produced an overall response rate of 73% in combination with BeiGene’s tisleizumab and chemotherapy in patients with advanced gastric cancer or GEA.

Cancer vaccines, which harness the body’s own immune system to fight cancer, represent a fast-growing market, with Precedence Research predicting a compound annual growth rate of 11.4% over the next decade. Here are a couple to keep a close eye on.

OSE Immunotherapeutics’ Tedopi

Phase III

Tedopi, a late-stage NSCLC vaccine, significantly improved OS over chemotherapy in a Phase III clinical trial, with a rate of 44.4%.

The vaccine is a novel T-cell epitope-based cancer vaccine that targets five tumor-associated antigens and stimulates the expansion of tumor-specific T cells.

A Phase III trial is planned to support the regulatory registration of Tedopi in patients in secondary resistance to immune checkpoint inhibitors of second-line NSCLC.

Merck and Moderna’s Personalized Melanoma Vaccine

Phase III

Skin cancers, including melanoma, are the most common form of cancer in the U.S.

Partners Merck and Moderna are initiating a pivotal Phase III high-risk melanoma trial that combines an mRNA-based personalized cancer vaccine with Keytruda. The vaccine is encoded with up to 34 neoantigens personalized to the unique mutation of each patient’s tumor.

In a Phase IIb trial, the combination reduced recurrence or death by 44% in treated patients compared to those who received Keytruda alone. The combo also reduced the risk of distant metastasis or death by 65%.

“We’re in an era of immunotherapy, which is really exciting,” Corridon said. “Immunotherapy has been moving in earlier [during treatment] which means patients are less sick and don’t have cancer for as long.”

Hayley Shasteen is a freelance science writer based in Northeastern Ohio. You can reach her at hayleyshasteen@gmail.com, or follow her on LinkedIn.