Response rates nearly double in phase 1 trials of cancer therapies
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Key findings:
- Researchers reported a treatment-related death rate of 0.7% for all phase 1 solid-tumor trials conducted through NCI’s Cancer Therapy Evaluation Program between 1991 and 2002.
- Investigators observed a 12.2% overall response rate and 2.7% complete response rate during the study period.
Response rates to investigational therapies evaluated in NCI-sponsored phase 1 trials for solid cancers have doubled over the past 2 decades, according to study results published in The Lancet.
Researchers reported no significant increase in treatment-related death rates among the phase 1 trials but cautioned that they did not see uniform improvements in response rates across all cancer types.
Investigators observed improvements in melanoma, bladder, breast and kidney cancer response rates during the study period, with no notable changes in response rates to novel therapeutics for pancreatic and colon cancer.
Background
The NCI’s Cancer Therapy Evaluation Program (CTEP) is a major sponsor of early-phase clinical trials via its network of participating centers in the U.S. and North America, according to Dai Chihara, MD, PhD, assistant professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center.
Analyses of response rates and treatment-related toxicity for NCI-sponsored phase 1 trials have not been published since 2005, in a study that evaluated trials conducted between 1991 and 2002. Those phase 1 trials showed response rates of approximately 5% to 10%, Chihara added.
“Cancer drug development has dramatically changed during our study period of 2000 to 2019 from a focus on cytotoxic chemotherapy to targeted agents, including monoclonal antibodies, small molecules and immunotherapy,” he told Healio. “Therefore, we aimed to see how these advances in drug development impacted the results of phase 1 trials.”
Methodology
Chihara and colleagues conducted a prospective study using data from investigator-initiated, NCI-sponsored phase 1 trials for solid tumors conducted through CTEP.
The analysis included patient-level data of 13,847 patients from 465 study protocols using 261 agents from Jan. 1, 2000, to May 31, 2019. Sixty-nine percent of trials used combination therapy, whereas 31% evaluated monotherapy.
Investigators collected data on overall response rates, complete response rates and treatment-related toxicity. The study included analyses over time based on cancer type and the investigational agent being evaluated.
Key findings
Researchers reported an overall treatment-related death rate of 0.7% (95% CI, 0.5-0.8) for all trials during the entire study period. The risk for treatment-related death did not change over time, the investigators noted.
Further analysis showed an 8% (95%, CI 7.6-8.5) risk for on-treatment death, regardless of whether the death was attributable to the investigational agent or other causes.
Investigators observed a 12.2% (95% CI, 11.5-12.8) ORR during the entire study period, which increased from 9.6% (95% CI, 8.7-10.6) between 2000 and 2005 to 18% (95% CI, 15.7-20.5) between 2013 and 2019.
The analysis showed a complete response rate of 2.7% (95% CI, 2.4-3) for the entire study period, increasing from 2.5% (95% CI, 2-3) between 2000 and 2005 to 4.3% (95% CI, 3.2-5.7) between 2013 and2019.
The researchers noted associations with higher ORRs using antiangiogenesis agents for bladder, colon, kidney and ovarian cancer, in addition to DNA repair inhibitors for ovarian and pancreatic cancer.
Clinical implications
The study’s results are limited by the nature of the trials included in the analysis, which includes mostly combination therapy trials conducted via NCI’s agreements with industry sponsors and collaborators conducting trials at academic medical centers, Chihara noted.
“Thus, ‘first-in-human’ single-agent trials are underrepresented in [our] study,” he told Healio. “To further characterize outcomes of modern phase 1 trials, collaborative work to build a more comprehensive and complete real-world database is warranted.”
Nevertheless, Chihara said the results show a near-doubling of ORRs among NCI-sponsored trials for solid tumors during the study period, which means newer-generation investigational therapies offer a higher likelihood of response with no greater risk for treatment-related death.
“We hope our study showed encouraging safety and response data in modern phase 1 trials for solid tumors and provided an important framework for oncologists to discuss participation with patients,” he said.
The results suggest that phase 1 clinical trials are a legitimate treatment option for patients with certain solid tumors in the age of immunotherapy and targeted molecular treatments, according to Antoine Italiano, MD, PhD, head of the early-phase trials and sarcoma units at Institut Bergonié in Bordeaux, France, and the precision oncology program at Gustave Roussy in Paris.
“The main goal of patients consenting to participation in phase 1 studies is to find effective treatments for their cancer. The main objective of the oncologists who refer them to the phase 1 study team is to offer them access to an innovative therapeutic opportunity,” Italiano wrote in an accompanying editorial. “Chihara and colleagues should be commended for having provided to the scientific community a clear demonstration that both groups are right in their choice.”
References:
- Chihara D, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)01390-3.
- Italiano A. Lancet. 2022;doi:10.1016/S0140-6736(22)01533-1.
For more information:
Dai Chihara, MD, PhD, can be reached at Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 6550 Fannin St., Houston, TX 77030.
Perspective
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Dale R. Shepard, MD, PhD, FACP
Chihara and colleagues should be applauded for updating the efficacy and safety data from NCI CTEP phase 1 trials. Phase 1 trials are the initial step for approval of new cancer drugs or combinations. An adequate understanding of the risks and benefits of these studies is crucial for patients considering enrollment and their oncologists who refer them to participate.The increased efficacy in these phase 1 trials likely is due to a number of factors, including novel therapies, patient selection and better supportive care. During the time period for this analysis, most of the novel therapies were not traditional chemotherapy, but targeted therapies, genomic therapies or immunotherapies. As CTEP trials, many used drugs that had shown benefit in prior studies or were trials enriched with patients having tumor types likely to respond.
It is particularly striking that the complete response rate was nearly 3% and as high as 4.3% during the last 6 years of the analysis.
Typically, phase 1 trials enroll patients who already have failed numerous lines of therapy. These rates of complete response are rare for most patients with solid tumors getting standard of care therapies in a second-, third- or fourth-line setting.
It is not surprising that patients with melanoma or bladder, breast or kidney cancers had the greatest benefit. These cancers are heavily represented in trials and most responsive to many of the newer targeted drugs and immunotherapies.
These data provide both hope and a call to action. In 2023, about 100,000 patients will die of advanced colorectal and pancreatic cancers. There is a shortage of phase 1 trials that enroll these patients. If these studies truly can offer benefit to patients, we must ensure inclusion of patients with an unmet need.
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