ASCO Names Molecular Profiling in GI Cancers as Advance of the Year

Howard A. “Skip” Burris, III, MD, FACP, FASCO

Molecular profiling has paved the way for several advances in the treatment of patients with gastrointestinal (GI) malignancies, by identifying critical markers and gene signatures that allow for the delivery of options that are personalized to each tumor. To this end, ASCO has chosen molecular profiling driving progress in GI cancers as its Advance of the Year.¹

The organization made the announcement as part of its Clinical Cancer Advances 2021: ASCO’s Annual Report on the Progress Against Cancer. The annual update shines a light on important clinical research milestones and policy developments that have been made over the past year; the report also spotlights areas of opportunity to address unmet needs with future efforts.

“Molecular profiling tools such as next-generation sequencing give us the ability to identify specific molecular and genomic-targeted treatments that are likely to benefit an individual patient,” Howard A. “Skip” Burris, III, MD, FACP, FASCO, ASCO board chairman, stated in a press release.² “Personalized medicine is becoming a reality.”

Although treatments such as surgery, radiotherapy, and chemotherapy have served as the mainstay of treatment in patients with GI cancers, these approaches have limited efficacy and can negatively impact quality of life, according to the report. Although the development of more effective approaches has lagged, the advent of molecular profiling has helped to expand options for these patients; this has resulted in longer survival with minimal adverse effects.

The ability to identify genetic abnormalities, such as mutations, amplifications, or fusions, as well as epigenetic profile, protein expression, or other molecular features has allowed for patients to be matched with the appropriate targeted therapy for their specific tumor. In the past year, HER2-targeted agents have been shown to improve survival in patients with gastric cancer; this approach is showing similar potential in patients with HER2-positive colorectal cancer (CRC).

Several HER2-targeted agents are being examined in patients with GI cancers. For example, the safety and efficacy of the novel HER2-targeted antibody–drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) was evaluated in patients with HER2-positive gastric or gastroesophageal cancers who had progressed on trastuzumab (Herceptin) as part of the phase 2 DESTINY-Gastric01 trial (NCT03329690).³

Patients who received trastuzumab deruxtecan achieved an objective response rate (ORR) of 51.3% versus 14.3% in those who received chemotherapy. Patients on the trastuzumab deruxtecan arm also experienced an improvement in median overall survival (OS) compared with those on the chemotherapy arm, at 12.5 months versus 8.4 months, respectively (HR, 0.59; 95% CI, 0.39-0.88; P = .0097). The benefit achieved with the ADC led to the January 2021 approval of trastuzumab deruxtecan for use in adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had previously received a trastuzumab-based regimen.⁴

Additional data on the agent were presented during the 2020 ASCO Virtual Scientific Program. In thephase 2 DESTINY-CRC01 study (NCT03384940), trastuzumab deruxtecan was examined in 78 patients with HER2-expressing, metastatic CRC who had progressed on 2 or more prior regimens. Here, 1 patient experienced a complete response to treatment, while 23 experienced partial responses.⁵ In this population, the agent yielded an ORR of 45.3%.

Another advancement was the June 2020 FDA approval of first-line pembrolizumab (Keytruda) for patients with microsatellite instability–high or mismatch repair deficient CRC.⁶ This regulatory decision on was based on the results from the phase 3 KEYNOTE-177 trial (NCT02563002), in which the PD-1 inhibitor was found to double the time to disease progression versus standard chemotherapy, at 16.5 months versus 8.2 months, respectively.⁷ Moreover, pembrolizumab resulted in a significant 40% reduction in the risk of disease progression or death versus chemotherapy (HR, 0.60; 95% CI, 0.45-0.80; P = .0004).

Equity in Clinical Cancer Trials

The report also examined health inequities in cancer care and clinical research. Although overall cancer-related mortality has decreased in the United States, underserved patient populations still experience lower survival; these populations include black patients, those residing in rural areas, and those with lower incomes and education levels.^8,9

“Disparities in cancer research is a complex, multifaceted issue requiring a multifactorial response that addresses (1) specific interrelated barriers precluding certain populations from trial participation, and (2) structural and systemic challenges that limit the cancer community’s pursuit of research that would benefit underserved populations,” the authors of the report write.

Some obstacles to equitable cancer research can include structural barriers, such as a lack of access to clinics offering clinical trials, as well as transportation and health insurance; clinical barriers, such as eligibility criteria; patient attitudes regarding trials, which could stem from historical inequities and a lack of informed consent; and physician attitudes, such as not offering underserved patients the opportunity to enroll to relevant clinical trials.

The authors of the report suggest several strategies to potentially improve equity in clinical cancer research. To this end, ASCO and Friends of Cancer Research have been working together to finalize 4 new Guidance for Industry documents that would broaden eligibility criteria for clinical trials by lowering the minimum participation age and to include patients with brain metastases who have been treated and are stable. Additionally, expanded guidelines would include patients with human immunodeficiency virus and hepatitis B and C virus, and recommend less restrictive renal, cardiac, and hepatic function criteria.

Other efforts include umbrella and basket trial designs, broadening trial availability, improving patient education and navigation, developing new consent strategies, and providing more financial assistance plans.

Artificial Intelligence Takes Center Stage

Among the numerous developments listed in the report, authors underscored the importance of artificial intelligence (AI) technology, a complex field of medical research that has grown exponentially in recent years. Authors of the report noted that AI technology can potentially be used to integrate a wealth of data points into a clinically meaningful context.

Currently, several types of AI are being utilized in the field of oncology, including deep learning methods that are able to identify relationships within data to solve complex problems through the utilization of algorithms in an iterative process. This technology could help to advance diagnostic, therapeutic, and translational research in both cancer prevention and treatment.

Key areas of interest include the development of deep learning methodologies to help with diagnosing cancer based on biospecimen analysis; using AI to improve radiographic imaging, analysis, and reporting; and using these systems to integrate vast amounts of clinical data to assist in the clinical decision-making process and measure outcomes.

“It will be critical to educate oncologist about the fundamentals, advantages, and potential pitfalls of AI and deep learning techniques to support effective application in real-world cancer care,” according to the authors of the report.

Challenges in Cancer Research During the COVID-19 Crisis

The coronavirus disease 2019 (COVID-19) pandemic has provided a unique opportunity for investigators to reconsider how clinical cancer research can be conducted and to examine disparities that exist with regard to clinical trial participation. Within the first weeks of the pandemic, 60% of US research institutions froze screening and enrollment for clinical trial research.¹⁰

To address this, investigators and institutions, with help from the FDA and the National Comprehensive Cancer Network, took action. To avoid the shutdown of clinical trials, investigator and sponsors found ways to allow for some flexibility, while preserving the integrity of the research. Remote patient monitoring and drug administration were permitted, and guidance was created to allow for virtual consent using e-signatures and limited collection of research-only biospecimens. Moreover, patients were allowed to have their local healthcare providers perform blood draws and imaging scans for these efforts.

Although the pandemic spotlighted existing racial and socioeconomic disparities, it also underscored the ability of the oncology community to rapidly respond to significant, unexpected disruptions to care and research efforts.

“This same ingenuity and flexibility can and should be applied to improving health equity for all individuals, so that right treatment truly is delivered to the right patient at the right time, everywhere,” the authors of the report wrote.

References

1. Smith SM, Wachter K, Burris HA, et al. Clinical cancer advances 2021: ASCO's report on progress against cancer. J Clin Oncol. Published online February 2, 2021. doi:10.1200/JCO.20.03420
2. ASCO names advance of the year: molecular profiling drives progress in gastrointestinal cancers. News release. ASCO. February 2, 2021. Accessed February 2, 2021.
3. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382:2419-2430. doi:10.1056/NEJMoa2004413
4. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed February 1, 2021. http://bit.ly/35KBZ8T
5. Yoshino T, Siena S, Di Bartolomeo K, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. Ann Oncol. 2020;31(suppl 6):S1273-S1286. doi:10.1016/annonc/annonc355
6. FDA approves Merck’s Keytruda (pembrolizumab) first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. News release. Merck. June 29, 2020. Accessed February 1, 2021. bwnews.pr/3ePxyfu.
7. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207-2218. doi:10.1056/NEJMoa2017699.
8. Henley SJ, Anderson RN, Thomas CC, et al. Invasive cancer incidence, 2004–2013, and deaths, 2006–2015, in nonmetropolitan and metropolitan counties — United States. Surveillance Summaries. 2017;66(14):1-13. doi:10.15585/mmwr.ss6614a1
9. Singh GK, Jemal A. Socioeconomic and racial/ethnic disparities in cancer mortality, incidence, and survival in the United States, 1950–2014: over six decades of changing patterns and widening inequalities. J Environ Public Health. Published online March 20, 2017. doi:10.1155/2017/2819372
10. Bakouny Z, Hawley JE, Choueiri TK, et al. COVID-19 and cancer: current challenges and perspectives. Cancer Cell. 2020;38:629-646. doi:10.1016/j.ccell.2020.09.018