Rising Standards in Regulatory Decisions Highlight Challenges in Drug Development in Lung Cancer

Author(s):

If the FDA’s Oncologic Drugs Advisory Committee meeting held on February 10, 2022, was any indication, the days of applying foreign single country or region data to support regulatory approval are gone; instead, regulatory decisions are headed toward the need for regional consistency through multiregional clinical trials, which could help the United States overcome the persistent underrepresentation of racial and ethnic minorities in drug development.

Jorge J. Nieva, MD

If the FDA’s Oncologic Drugs Advisory Committee (ODAC) meeting held on February 10, 2022, was any indication, the days of applying foreign single country or region data to support regulatory approval are gone; instead, regulatory decisions are headed toward the need for regional consistency through multiregional clinical trials, which could help the United States overcome the persistent underrepresentation of racial and ethnic minorities in drug development.¹

In the meeting, ODAC voted against using single-country foreign data to support the biologics license application for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer (NSCLC).

The committee stated that because the phase 3 ORIENT-11 trial (NCT03607539), which demonstrated a progression-free survival benefit vs chemotherapy alone (HR, 0.48; 95% CI, 0.36-0.64; P < .00001),² was conducted entirely in China, it could not be applied to the US population. In a 14-1 vote, the committee required drug maker Innovent Biologics to launch a new trial demonstrating the efficacy of sintilimab, an anti–PD-1 monoclonal antibody, in the US.

“[The decision not to use single country data] ignores the biggest problem in health care disparities, which is the cost of the medicines that we give our patients. The cost of the medicines that we give our patients is in large part driven [by the fact that] we’ve made medical research exorbitantly expensive. When you look at the cost of a drug approval today, we’re now looking at about $2.6 billion dollars, and this is up 20-fold from where it was in the 1970s in constant dollars. But we’ve made our trials extraordinarily complex. Now looking at more end points or procedures, we now have on average about 50 eligibility criteria to treat patients in clinical trials,” Jorge J. Nieva, MD, said in a presentation at the 20th Annual Winter Lung Cancer Conference®.

In his presentation regarding the applicability of foreign clinical trial data to a US lung cancer population, Nieva, an associate professor of clinical medicine at Keck School of Medicine at the University of Southern California in Los Angeles, discussed the importance of understanding how this continues to drive current gaps in diverse clinical trial enrollment.

In a paper published in the Journal of Medical Economics, authors concluded that an approximated 375,256 lung cancer–related deaths were avoided due to new cancer medicines in the US between 2000 and 2016.3 However, the patients who may benefit from such treatment do not have access to them. That, coupled with disparities in clinical care and research, has led to poorer outcomes in minority populations. This was documented in a 2021 report from the American Lung Association, which showed that people of color who receive a diagnosis of lung cancer have worse outcomes compared with White Americans.⁴

Disproportionate outcomes can also be traced in part to disparities in biomarker testing. In an abstract presented at the 2021 ASCO Annual Meeting, investigators documented that 50.1% (n = 4,904) of White patients with NSCLC received next-generation sequencing compared with only 39.8% (n = 513) of Black/African American patients (P < .0001).5 Additionally, investigators showed that more Black/African American patients were receiving carboplatin and paclitaxel as frontline therapy than White patients. “There’s very few situations where carboplatin and paclitaxel should be the standard of care,” Nieva said.

Gaps in clinical trial enrollment have also been well established, but not for reasons many might expect, Nieva noted. In an analysis presented at the 2021 ASCO Annual Meeting by Bruno et al, investigators showed that approximately twice as many White patients with NSCLC were enrolling in clinical trials compared with Black/African American patients (P = .0002). However, another study from Raymond U. Osarogiagbon, MBBS, et al demonstrated that Black, Hispanic, and Asian patients were more likely to enroll in a clinical trial if offered one compared with White patients.6

“The main reason people don’t participate in clinical trials is, number one, there is no clinical trial available to them. Trials aren’t offered in their neighborhood, they’re not offered by their physician or by their health-care system,” Nieva said.

This becomes important when one considers the prevalence of actionable biomarkers among different races. For example, a study published in 2022 showed that approximately half of Asian patients (n = 142) have EGFRor TP53 mutations.7

“You probably have to do multiregional clinical trials these days, and you need to have your clinical trial approved by the FDA ahead of time. The single-country data [are] only going to be acceptable in areas where the trial can’t be done in a multiregional setting. We all need to focus on external validity, and there are lots of ways of getting there. We do need to focus on pricing competition for these agents if we want to reduce health care disparities,” Nieva concluded.

Editor’s Note: Dr Nieva has received research funding from Genentech/Merck and has consulted for Aadi Biosciences, AstraZeneca, Bristol Myers Squibb, Fujirebio, G1 Therapeutics, Genentech, Kalivir, Mindmed, Naveris, Takeda, Western Oncolytics, and Ypsomed.

References

Singh H, Pazdur R. Importing oncology trials from China: a bridge over troubled waters? Lancet Oncol. 2022;23(3):323-325. doi:10.1016/S1470-2045(22)00071-7
Yang Y, Wang Z, Fang J, et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020;15(10):1636-1646. doi:10.1016/j.jtho.2020.07.014
MacEwan JP, Dennen S, Kee R, et al. Changes in mortality associated with cancer drug approvals in the United States from 2000 to 2016. J Med Econ. 2020;23(12):1558-1569. doi:10.1080/13696998.2020.1834403
American Lung Association: State of Lung Cancer 2021. Accessed February 6, 2023. https://www.lung.org/getmedia/ba972351-ddc5-46b2-8e0d-028002d16c72/solc-2021-print-report-final.pdf
Bruno DS, Hess LM, Li X, et al. Racial disparities in biomarker testing and clinical trial enrollment in non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;31(15):9005. doi:10.1200/JCO.2021.39.15_suppl.9005
Osarogiagbon RU, Sineshaw HM, Unger JM, et al. Immune-based cancer treatment: addressing disparities in access and outcomes. Am Soc Clin Oncol Educ Book. Published online April 8, 2021. doi:10.1200/EDBK_323523
Hsu R, Herrmann A, Gaur K, et al. Evaluating real world mutational differences between Hispanics and Asians in NSCLC at a large academic institution in Los Angeles. Clin Lung Cancer. 2022;23(7):e443-e452. doi:10.1016/j.cllc.2022.06.007