Quantifying the Benefits of Precision Oncology

Publication
Article
Targeted Therapies in OncologyNovember 2018
Volume 7
Issue 11

Precision medicine has produced some dramatic successes in patients with advanced cancer. With developments in molecular profiling, targeted therapies are being applied to multiple tumors, most notably in advanced melanoma, NSCLC, and several types of leukemia. Alison Schram, MD, and David M. Hyman, MD, point out the challenges in determining the proportion of patients who will benefit from receiving targeted therapies.

Precision medicine has produced some dramatic successes in patients with advanced cancer. With developments in molecular profiling, targeted therapies are being applied to multiple tumors, most notably in advanced melanoma, non—small cell lung cancer (NSCLC), and several types of leukemia.

But questions have remained about how many patients with advanced or metastatic cancer benefit from all these genomic advances in precision medicine. Some oncology researchers—including Alison Schram, MD, a medical oncologist; and David M. Hyman, MD, the chief of the Early Drug Development Service, both at Memorial Sloan Kettering Cancer Center in New York, New York—point to the many challenges in determining the proportion of patients who benefit from receiving targeted therapies.1

“[These challenges include] patient heterogeneity, the genomic profiling techniques applied, matching criteria used, drugs selected, and reliability of access to these drugs, all of which can influence the measured impact of precision medicine,” Schram and Hyman wrote in the June 2017 issue of Cancer Discovery.

Despite these challenges, researchers at Oregon Health & Sciences University (OSHU) in Portland, Oregon, estimated the percentage of patients eligible for genome-informed and genome-targeted therapies, from January 2006 to January 2018, and the overall percentage of patients who benefitted from these therapies in a retrospective cross-sectional study using publicly available data.2

Since 2006, the FDA has approved at least 31 precision medicine—related cancer drugs with a total of 38 indications—28 of those are considered genome-targeted therapies, or drugs prescribed based on aberrations identified in a genomic test.2 One example of such an approval is the PARP inhibitor olaparib (Lynparza), which was approved in 2014 for the treatment of patients with deleterious germlineBRCA-mutated advanced ovarian cancer. The remainder of the drugs are “genome informed”—including those considered genome targeted—given after a patient has undergone genomic testing, regardless of whether the drug targets abnormalities or mutations identified on the test.

To estimate the benefit to patients, the researchers determined the number of patients who died based on annual mortality statistics by cancer type from the American Cancer Society, then looked at the annual median response rate of individual drugs from clinical trials.

The OSHU team found that the percentage of patients eligible for genome-targeted therapies has increased steadily since 2006, from 5.09% (95% CI, 5.03%-5.14%), or 28,729 of 564,830 patients, to 8.33% (95% CI, 8.26%-8.40%), or 50,811 of 609,640 patients.

The researchers attributed the increase in patient eligibility to the FDA approvals for both crizotinib (Xalkori), in the treatment of patients with NSCLC harboring ALK rearrangements, and the BRAF inhibitor vemurafenib (Zelboraf) in the treatment of BRAF V600E—positive metastatic melanoma. Patient eligibility jumped again in 2017 after the FDA approved the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) for the treatment of patients with BRAF V600E–positive metastatic NSCLC; and enasidenib (Idhifa) and midostaurin (Rydapt) targeting IDH2 and FLT3, respectively, in acute myeloid leukemia (AML).

Perhaps because of the broader definition of genome-informed therapies, 10.5% (95% CI, 10.42%-10.58%) or 59,301 of 564,830 patients were eligible in 2006, which increased to 15.44% (95% CI, 15.35%-15.53%) or 94,157 of 609,640 patients by 2018. Genome-informed therapies experienced a jump when the FDA approved anti—PD-1 drugs nivolumab (Opdivo) and pembrolizumab (Keytruda) for colorectal cancer and other solid tumors harboring high microsatellite instability.

But the investigators estimated that only a small minority of patients would have benefitted from genome-informed or genome-targeted therapies, even in 2018. Only 4.90% (95% CI, 4.85%-4.95%), or 29,899 of 609,640 patients, would have benefited from genome-targeted therapy in 2018. This represented a 7-fold increase from 0.70% (95% CI, 0.68%-0.72%), or 3,965 of 564,830 patients, in 2006 (FIGURE 12). Only 6.62% (95% CI, 6.56%-6.68%), or 40,349 of 609,640 patients, have benefited from genome-informed therapy since the start of 2018, and this represents a 6-fold increase compared with 1.31% (95% CI, 1.28%-1.34%), or 7,396 of 564,830 patients, in 2006.2

“Of all Americans estimated to die of cancer in 2018, just 8.33% are at best eligible for genomic-targeted therapy, and at best 4.9% will respond to these drugs. This assumes that 100% of patients are tested, are given the drugs for free, and several other optimistic assumptions we described in the paper. As a result, the true numbers will be lower,” principal investigator Vinay K. Prasad, MD, MPH, a hematologist-oncologist and an associate professor of medicine at OSHU, said in an interview with Targeted Therapies in Oncology.

One of the reasons for this low number is that “there are still many types of mutations without an effective targetable drug, or mutations that appear tissue or microenvironment dependent,” Andrew Davis, MD, an oncology-hematology fellow at Northwestern University Feinberg School of Medicine, said in an interview with Targeted Therapies in Oncology. For example, the drug vemurafenib targetsBRAFmutations but has produced different response rates in clinical trials across tumor types.

On a more optimistic note, Davis added that “although a small percentage of patients are benefiting from genome-driven targeted therapies, the percentage has increased over time.” He attributed the increase to identifying known driver mutations with clearly effective targeted therapies, which have also increased over time because of drug development.

Although next-generation sequencing (NGS) is a promising approach to increase patient access to targeted therapies, Prasad and his coauthors noted in their paper that barriers to success include cost, harms, and missed opportunities for conventional therapies.1

Next-Generation Sequencing

A debate in the oncology field is whether conducting molecular profiling in patients with advanced cancer or metastatic solid tumors is necessary.

“It’s clear that FDA-approved, standard-of-care drugs should be offered to patients with known mutations. When a patient progresses beyond the standard of care with metastatic disease, it’s worthwhile to do comprehensive genomic sequencing to see if additional targets and trials are suitable for those patients,” Davis said.

The IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy; NCT00851032) clinical trial began in 2007 and analyzed the impact of personalized therapy based on molecular testing of tumors for patients with difficult-to-treat cancers. The most common types of cancers included in the study were gastrointestinal, gynecologic, breast, lung, and thyroid cancers, as well as melanoma.

“Our findings show that molecular testing of tumors with next-generation sequencing can be used to optimize therapy and should be taken into consideration when selecting therapy for patients with difficult-to-treat cancers,” said lead study author Apostolia Maria Tsimberidou, MD, PhD, a tenured professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston.3

In the later years of the study, which lasted through the end of 2013, NGS was used to test 20 to 50 genes at once. Among the 3743 patients who had molecular testing, at least 1 genetic change was found in 1307 tumors. Of the patients with an identified genetic change, 711 received a treatment that matched the biology of their tumor, and 596 did not because no matched treatment was available at that time. Matched therapies were most commonly an investigational drug being tested in a clinical trial, including single-agent targeted therapy, matched-targeted therapy in combination with chemotherapy, or other treatments.

The researchers found that using molecular tests of tumors to select targeted therapy resulted in slower cancer growth and prolonged survival across a diverse set of cancer types.

The 3-year overall survival (OS) rate was 15% in the matched-targeted group, compared with 7% in the nonmatched group. The 10-year OS rate was 6% for the matched group and 1% in the nonmatched group. OS in the matched group plateaued, starting at 3.2 years with 11% surviving at follow-up.

The ongoing National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest precision medicine trial of its kind, is looking at whether targeted therapies for patients whose tumors have certain genetic mutations will be effective regardless of their cancer type (FIGURE 2). Researchers use a DNA sequencing test to identify gene mutations in patients’ tumors. The test looks for mutations in 143 genes associated with cancer that can be targeted by one of the drugs being studied in the trial. The trial started in August 2015 and includes nearly 40 treatment arms, each of which aims to enroll at least 35 patients whose tumors have a specific genetic change, according to an NCI press release.4

“NCI-MATCH represents the first attempt to systematically leverage next-generation sequencing to explore so many therapies in parallel,” ECOG-ACRIN study chair Keith T. Flaherty, MD, a medical oncologist at Massachusetts General Hospital Cancer Center in Boston, said in the news release. “By focusing our investigational effort on new biomarker-guided therapies in understudied cancer types, we have accelerated the opportunity to find signals of efficacy.”

Clinical trials are also being designed to test a single drug that targets specific mutations detected by molecular profiling in many cancers. For example, a recent paper published in the New England Journal of Medicine showed that the drug larotrectinib had marked and durable antitumor activity in patients with TRK fusion—positive cancers, regardless of the age of the patient or the tumor type.5“TRK fusion occurs in less than 1% of all cancers but is present in many types of cancers in adults and children. The response rate to the drug was remarkable, between 75% and 80%,” Davis said.

A total of 55 patients were enrolled and treated in the study and ranged in age from 4 months to 76 years. Patients had 17 unique TRK fusion—positive tumor types, which was detected by NGS. The investigator-assessed overall response rate was 80% (95% CI, 67%-90%) and 75% (95% CI, 61%-85%), according to independent review. At 1-year follow-up, 71% of the responses were ongoing, and 55% of the patients remained progression free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of patients responding (38 of the 44 patients) were continuing treatment or had undergone curative surgery.

Overcoming the Hurdles

Davis anticipates that in the next few years, the percentage of patients who benefit from targeted therapy will increase. “The cost of genomic sequencing will continue to decrease. That, combined with greater availability of targetable drugs and improved research about what genomic mutations are doing, can [only] point to an increase.”

Tsimberidou and her colleagues are currently conducting IMPACT 2, a randomized study evaluating molecular profiling and targeted agents in patients with metastatic cancer (NCT02152254). The application of precision medicine techniques using NGS hold the promise to significantly improve the clinical outcomes of patients with cancer, she noted in the ASCO statement.

Prasad said that a lack of drugs is the main barrier to implementing precision medicine. “We should develop and fund new trials of genomic therapies along with broader cancer drug portfolios, including immunotherapeutic and cytotoxic approaches,” he said.

He cautioned that only a fraction of cancer patients who desire these drugs will be eligible for FDA genome-directed cancer therapies, and only a fraction of those patients will experience a response. “Proponents of precision medicine are misleading the public by talking about exponential growth or by saying ‘We are reaching an inflection point.’ It has been slow, steady growth.

References:

  1. Schram AM, Hyman DM. Quantifying the benefits of genome-driven oncology. Cancer Discov. 2017;7(6):552-554. doi: 10.1158/2159-8290.CD-17-
  2. Marquart J, Chen EY, Prasad V. Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology. JAMA Oncol. 2018;4(8):1093-1098. doi: 10.1001/jamaoncol.2018.1660.
  3. 2018 ASCO: IMPACT trial matches treatment to genetic changes in the tumor to improve survival across multiple cancer types. The ASCO Post website. ascopost.com/News/58897. Published June 2, 2018. Updated June 6, 2018. Accessed October 30, 2018.
  4. NCI-MATCH precision medicine clinical trial releases new findings, strengthens path forward for targeted cancer therapies [news release]. Bethesda, MD: National Cancer Institute; June 4, 2018. cancer.gov/news-events/press-releases/2018/nci-match-first-results. Accessed October 30, 2018.
  5. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.
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