Despite the coronavirus disease 2019 pandemic, major progress in cancer research has been made in the past year in the areas of molecular profiling, biomarker-driven treatment approaches, targeted therapies brought into earlier stages of disease, treatment combinations with limited toxicities, and treatments that extend survival for hard-to-treat cancers.
Despite the coronavirus disease 2019 (COVID-19) pandemic, major progress in cancer research has been made in the past year in the areas of molecular profiling, biomarker-driven treatment approaches, targeted therapies brought into earlier stages of disease, treatment combinations with limited toxicities, and treatments that extend survival for hard-to-treat cancers, according to the American Society of Clinical Oncology (ASCO). However, equity in cancer treatment and care still needs to be achieved.1,2
The Issue of the Year
Due to early detection, prevention measures, treatment, and decades of research, cancer mortality rates have been dropping overall in the United States. However, lower income patients, those living in rural areas, populations with lower education levels, and Black patients still experience lower survival rates and higher mortality rates for many cancer types.
According to the 16th annual report, “Clinical Cancer Advances 2021: ASCO’s Report on Progress Against Cancer,” disparities in care are, in many respects, connected to the development of novel therapeutics and diagnostics. Most patients with cancer express a willingness to participate in clinical trials and research. However, only 8% of adult patients with cancer are enrolled in clinical trials with the percentage of minorities participating in trials, overall, much lower when compared to the general population.
In the pediatric space, clinical trials have always been more diverse, with over 50% of the enrollment of affected children being from a diverse background. This diversity has contributed to a decline in pediatric cancer deaths over the past 4 decades.
Recent analysis has found that only between 4% to 6% of adult clinical trial participants are Black while only 3% to 6% are Latino, despite representing 15% and 13% of all patients with cancer, respectively. This disparity fails to provide the evidence needed for clinicians to safely treat minority patients with cancer.
“I think this has been a quite an impactful year. Certainly, racism and open displays of racism, while they are not new, they have become far more evident to a larger group of people because they were on our TVs, thanks to people capturing things on their cell phones. A lot more people became aware of them. And so, there is a dialogue. That is a very positive step forward in terms of people discussing the fact that inequitable care exists within our healthcare system,” said ASCO president Lori J. Pierce, MD, FASTRO, FASCO, in an interview with Targeted Oncology.
According to Pierce, the policies currently in place in our health care system are largely at fault for cancer care and survival disparities. Minority patients are more likely to be on Medicaid, which currently does not cover the routine care costs related to clinical trials and research. Both Medicare and private insurance covers these costs, but Medicaid does not. This excludes many economically disadvantaged people from clinical trials.
“We want as many patients as possible to be enrolled in clinical trials because clinical trials give you the opportunity to get the best possible care existing and/or the care that has been shown in preliminary trials to be as good, if not better, than the current standard of care. So, you will get excellent care in clinical trials. And we know it's important for patients and clinical trials not only to get excellent care, but also to be able to have a wide spectrum of patients on trial,” Pierce said.
The Clinical Treatment Act, which has bipartisan support, has been passed as a part of the COVID-19 relief legislation.3
The COVID-19 pandemic has also had a drastic impact on cancer care, with many patients canceling routine screenings, labs being shut down, and clinical research in some places halting. According to Pierce, there is a concern that there will be a spike in cancer cases and deaths in a few years as a result of the pandemic. However, the COVID-19 pandemic has also taught care providers things as well.
“During the course of the pandemic, we also realized that it's easier for some patients to interact to some degree by telemedicine; [for] our patients in rural communities it was difficult for them to come in. There may be some parts of their therapy that we can do at a distance, there may be ways that we can [do this] for those patients in clinical trials to [help] them receive some of their medications… at facilities closer to them,” Pierce said.
As a result of the pandemic, the cancer care and research community is learning to become more flexible and find ways to continue offering patients quality care and continue clinical trial participation, even remotely.
Advances of the Year
Despite a long way to go when it comes to cancer research and survival equity, there is good news. ASCO named molecular profiling for the treatment of gastrointestinal (GI) tumors, which account for 35% of all cancer-related deaths, as the major advance of the year in cancer research. According to the report, surgery, radiotherapy, and chemotherapy have been the standards of care for patients with GI tumors. However, these therapies often take a heavy toll on life while having limited effects. Additionally, the development of more effective therapies has lagged behind that of other tumor types.
“The [advancement] that was noted the most was the progress that has been made in treating GI cancers. And this is important because GI cancers account for about 25%, 26% of cancers in the world, and about 35% of all cancer-related deaths, so these are there a lot of cancers and deaths related to the GI tract,” said Pierce. “And these are cancers where surgery, radiation, and chemotherapy has been the mainstay of treatment. And while that's been effective in some, it has not been effective at all. And so, this year, the report really highlighted some of the advances, particularly in gastro-esophageal cancers.”
This has changed recently with improvements in molecular testing. Research conducted in the past year has found that targeting HER2, a protein that promotes cancer cell growth and occurs in about 20% of gastric and gastroesophageal cancers, can help improve survival in not only HER2-positive gastric cancer, but also in patients with HER2-positive colorectal cancer (CRC).
Trastuzumab deruxtecan (Enhertu), a novel antibody-drug conjugate (ADC) that links anti-HER2 trastuzumab (Herceptin) to the anticancer drug deruxtecan, plus chemotherapy is currently the standard initial treatment for HER2-positive gastric and gastroesophageal cancers.
In the phase 2 DESTINY-Gastric01 (NCTO3329690), 125 patients were randomly assigned to receive trastuzumab deruxtecan or the treating clinician’s choice of chemotherapy. Over half (51.3%) of the patients who received the ADC experienced an objective response, compared with the 14.3% of patients who received chemotherapy alone. Additionally, median overall survival (OS) was 4.1 months longer in the combination group when compared with chemotherapy (12.5 vs 8.4 months, respectively; HR, 0.59; 95% CI, 0.39-0.88; P = .01).4
Trastuzumab deruxtecan was approved by the FDA in January 2021 for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal adenocarcinoma who have received a prior trastuzumab-based regimen, and may help fill a significant unmet need for patients in this setting.5
The ADC was also investigated in the treatment of patients with HER2-expressing metastatic CRC that has progressed following 2 or more prior treatment regimens in the phase 2 DESTINY-CRC01 trial (NCT03384940). In this setting, trastuzumab deruxtecan led to an objective response rate of 45.3%, the median progression-free survival (PFS) was 6.9 months, and the median OS was not yet reached.6
Progress has also been made in CRC toward treating microsatellite instability. Approximately 5% of patients with metastatic CRC have high microsatellite instability or mismatch repair deficiency (MSI-H/dMMR). According to the report, this can be detected when a cell is unable to repair mistakes that are made during the DNA copying process. This causes DNA mutation to start accumulating in the cells and may cause cancer.
Pembrolizumab (Keytruda), an immune checkpoint inhibitor, blocks the activity of the receptor PD-1. This protein helps to keep the immune system in check, allowing it to fight cancer cells. The phase 3 KEYNOTE-177 trial (NCT02563002) found that in the first-line setting in patients with metastatic CRC and MSI-H/dMMR, pembrolizumab doubled the time to disease progression (16.5 months), compared with those who received conventional chemotherapy (8.2 months) (HR, 0.60; 95% CI, 0.45-0.80; P = .0002).7
Major advances were also made in the area of CRC prevention in patients with Lynch syndrome. In this patient population, the lifetime risk of CRC is estimated to be between 20% and 80% compared to the 4% to 5% in the general population. A 20-year follow-up of the CAPP2 study (ISRCTN59521990) found that daily aspirin greatly reduced the risk of developing CRC in patients with Lynch syndrome.8
The study included 427 patients who were randomly assigned to receive daily aspirin or placebo for 2 years. The analysis found that aspirin reduced the risk of colorectal cancer by 44% compared with placebo. Although the benefits took more than 5 years to be become detectable, they persisted beyond 20 years. Serious adverse events were comparable between the 2 groups and optimal dosage has yet to be determined.
The report also detailed further advances in combination and targeted therapies across tumor types. Recent developments include tucatinib (Tukysa) plus standard therapy of trastuzumab and capecitabine which helped to delay the progression of brain metastases in patients with HER2-positive breast cancer, which was found to improve overall survival by 6.1 months compared with placebo.
Another study found that immunotherapy before surgery may improve the prognosis of patients with early-stage triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. The phase 3 KEYNOTE-522 trial (NCT03036488) in patients with stage II or III TNBC found that the addition of neoadjuvant pembrolizumab to chemotherapy caused a pathologic complete response rate of 64.8% compared with 51.2% with chemotherapy alone (P < .001).9
Notable targeted therapy advancements include trastuzumab deruxtecan also for the treatment of patients with HER2-positive non–small cell lung cancer (NSCLC), as seen in the phase 2 DESTINY-Lung01 trial (NCT03505710). In the study, trastuzumab deruxtecan caused a confirmed response in 61.9% of trial participants and disease control in 90.5%; the estimated median PFS was 14 months.10
Additionally, adjuvant osimertinib (Tagrisso) doubled disease-free survival in patients with stage II to IIIA EGFR-positiveNSCLC in the phase 3 ADAURA trial (NCT02511106), leading to the FDA approval of the adjuvant in this setting in December 2020. In the study, surgery followed by osimertinib led to a 2-year disease-free survival rate of 90% compared with 44% in patients who received placebo instead, reducing the risk of disease recurrence or death by 83% (HR, 0.17; 95% 99.06% CI, 0.11-0.26; P < .001).11
Prostate cancers have also seen progress in the form of next-generation androgen receptor inhibitors in patients with castration-resistant disease as well as with PARP inhibitors for men with hormone therapy–resistant disease and mutations in DNA repair genes.
Priorities for Future Success in Cancer Research
According to ASCO, the future of cancer research should focus on the development of artificial intelligence and identifying strategies to help predict if a patient is resistant to immunotherapies, among other priorities to continue to propel cancer research forward.
The organization also noted that care can be optimized for older patients with cancer with acceptance of geriatric assessments and an understanding of the impact of treatment on older adults. Additionally, the treatment of pediatric and rare cancers could benefit from an increased research into precision medicine approaches for these patients.
The focus from this past year on equity will also continue in cancer research, the report suggested, as cancer clinical trials are encouraged to include more under-represented populations. The organization stressed that the barriers to trial enrollment need to be understood so that novel strategies can be implemented to overcome them to ensure that every patient with cancer benefits from cancer research.