Dylann Cohn-Emery

In a draft guidance for clinical investigators and sponsors, the FDA made recommendations on how to expand eligibility to patients with incurable cancer through clinical trial designs of investigational cancer drugs and biological products with the document “

Cancer Clinical Trial Eligibility Criteria: Available Therapy in Non-Curative Settings

“…The FDA issued a draft guidance encouraging industry to include patients with incurable cancers—when there is no potential for cure or for prolonged/near normal survival—in cancer clinical trials, regardless of whether they have received existing alternative treatment options,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Historically, many clinical trials have required that participating patients previously received multiple therapies.”

Once finalized, the recommendations in the draft guidance will help sponsors and investigators include more patients who have not received available the therapy or therapies in the non-curative setting. In this guidance, non-curative is defined as either unresectable, locally advanced, or metastatic disease in solid tumors, or hematologic malignancies with unfavorable long-term overall survival.

However, patients who are eligible for available therapies that could potentially cure their disease, such as in pediatric acute lymphoblastic leukemia, testicular cancer, or classic Hodgkin’s lymphoma, should receive those treatments before being eligible for a clinical trial. If they do not receive these therapies before an investigational cancer treatment, they may be exposed to unreasonable or significant risk of illness or injury.

“The FDA believes patients with incurable cancers, if provided adequate information to make an informed decision, should be eligible to participate in oncology clinical trials,” Pazdur said in a press release.

 “If there is no scientific rationale for excluding these patients, then clinical trial eligibility criteria should be broadened to include these patients, with appropriate informed consent.”

This FDA guidance states that patients who have not received the available therapies in the non-curative setting could be eligible for inclusion on first-in-human trials and beyond through the expansion of the eligibility criteria and the appropriate informed consent.

 Consent includes “a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject,” according to FDA standards. This informed consent must clearly state that other treatment options that offer clinical benefit are available and also include a discussion of potential risks, benefits, and uncertainties associated with the study drug.

Additionally, the FDA recommends evaluating patients who have not received the available therapies in separate cohorts from patients who were already given the available treatments in their setting. This is especially recommended for trials where the efficacy results need to be interpreted in a homogenous patient population. This separation could also be done using pre-specified subgroup analyses that have been defined before patients receive the trial drug or treatment.

“This draft guidance is part of the FDA’s broader initiative to encourage rational expanded patient eligibility for oncology clinical trials,” Pazdur concluded.

1. FDA in brief: FDA encourages inclusion of patients with incurable cancer in oncology clinical trials regardless of prior therapies. FDA. Published June 24, 2021. Accessed July 12, 2021. 

2. Cancer clinical trial eligibility criteria: available therapy in non-curative settings. FDA. Published June 24, 2021. Accessed July 13, 2021. 

Articles

In a draft guidance for clinical investigators and sponsors, the FDA made recommendations on how to expand eligibility to patients with incurable cancer through clinical trial designs of investigational cancer drugs and biological products.

FDA Recommends Including Patients on Trials Regardless of Prior Therapies in the Non-Curative Setting

A prospective analysis demonstrated a trend toward worse prognosis for patients with metastatic breast cancer (mBC) who were initially HER2 negative and switched to HER2 positive treated with HER2-directed therapies compared with those who were HER2 positive at diagnosis.

“Metanalyses have demonstrated that 5% to 10% of patients with initially HER2-negative disease switch to HER2 positive through the course of the disease in the metastatic setting,” Hans-Christion Kolberg, MD, PhD, said during a presentation of the data at the 2021 American Society of Clinical Oncology Annual Meeting. “These patients are treated with the same HER2-directed approaches as patients initially HER2 positive. Although, it is not known if they benefit from those approaches the same way.”

In the advanced breast cancer registry trial PRAEGNANT (NCT02338167), 49 patients with 

 fit the inclusion criteria and were evaluated to see if their baseline HER2 status of either negative or positive in their primary tumor had a prognostic value on overall survival (OS) and progression-free survival (PFS) after treatment with pertuzumab (Perjeta).

There were 4061 patients registered to PRAEGNANT by January 2021, 59 of which had HER2-positive and metastatic disease. Patients were excluded if they had: negative or unknown HER2 status, therapy with an investigational drug in a clinical study, unknown date of first metastasis, no documented therapies, and unknown HER2 primary tumor status. From that group, 10 patients who had no observation time were excluded.

For these patients, there was a median observation time of 9 months (96% CI, 3.8-23.7). Thirty-five PFS events occurred over 4 years of observation. HER2 status at baseline showed no significant effect, with a likelihood ratio test 

value of .07. Patients with initially HER2-positive disease had a longer PFS survival time compared with patients with initially HER2-negative disease (adjusted HR, 0.49; 95% CI, 0.24-1.03;

 = .06). The 1- and 2-year PFS rates were lower for patients who were HER2 negative at diagnosis, with a median PFS of 7.8 months in the negative group and 10.0 months in the positive group.

The OS median observation time was 24.2 months (95% CI, 11.7-37.6). During 48 months of observation time, 12 events occurred, which meant only the unadjusted model was evaluable. There was no significant effect of HER2 status (unadjusted HR, 0.49; 95% CI, 0.16-1.53; 

= .22). However, patients with positive HER2 status at primary diagnosis tended to have longer OS than those who were negative at diagnosis. There were slightly higher survival rates for the HER2-positive group as well.

According to Kolberg, the lead author of the analysis, “The number of patients switching from HER2 negative to HER2 positive in this analysis was higher than is known from the analysis published before and the median PFS, the 1-year, and the 2-year PFS rates appear to be better in patients initially HER2 positive.”

There were 43 patients (87.8%) with hormone receptor-positive status. Thirty-four patients had HER2-positive primary tumors, 9 had luminal A like tumors, and 6 had luminal B-like tumors. There were 29 of the 49 patients treated with chemotherapy, 3 who received pretreatment with pertuzumab, 22 pretreated with trastuzumab (Herceptin), 1 pretreated with TDM1, 1 pretreated with lapatinib (Tykerb), and 27 treated with antihormone therapy, all in either line 10 or 14.

The median age in this analysis was 56 years (range, 48-64) and all of the patients were women. There was a median body mass index of 25.2 (range, 22.8-30). The median time from diagnosis to first-line therapy was 4.5 years (range, 3.2-8.6).

“Our results have to interpret with caution because of the small cohort and the prospective nature of the analysis, but they definitely justify a prospective research, including the group of initially HER2 negative patients switch to HER2 positive as a distinct entity,” Kolberg concluded.

Kolberg H-C, Yüksel Ö, Fasching PA, et al. Comparison of therapy benefit from standard anti-HER2 directed approaches in metastatic breast cancer (MBC) between initially HER2-positive patients and patients initially HER2-negative with switch to HER2-positive. 

A prospective analysis demonstrated a trend toward worse prognosis for patients with metastatic breast cancer who were initially HER2 negative and switched to HER2 positive treated with HER2-directed therapies compared with those who were HER2 positive at diagnosis.

HER2+ Status at Diagnosis in Patients With mBC Shows More Favorable PFS Than HER2-Negative Status

In a retrospective analysis of patients with advanced non–small cell lung cancer (NSCLC) and 

 mutations treated with osimertinib (Tagrisso), investigators found that body mass index (BMI) of 25 kg/mq2 or more had a negative impact on survival outcomes.

The single-center study was performed in Bologna, Italy, and published as an abstract at the 2021 American Society of Clinical Oncology Annual Meeting. It investigated the standard of care in patients with EGFR tyrosine kinase inhibitor (TKI) naïve disease and in those with an 

 T790M mutation who had progressed following a prior EGFR TKI. Previously, there have been no clear data supporting the relationship between BMI and the efficacy of osimertinib.

From February 2016 to December 2020, 37 patients with advanced 

-mutated NSCLC who received osimertinib as second or later line therapy were examined for 

. They were split into either the BMI-high group of 25 kg/mq2 or more and a BMI-low group of less than 25 kg/mq2.

After a median follow-up for this study was 32.5 months (IQR, 13.35-42.06), there was a median overall survival (OS) of 29.9 months (95% CI, 18.2–not reached [NR]) for the whole group. Overall, the median progression-free survival (PFS) was 17.5 months for all patients (95% CI, 15.7-33.3).

There were 25 patients in the BMI-low group and 12 patients in the BMI-high group. In the BMI-low, median PFS was 21.0 months (95% CI, 16.8-NR) and in the BMI-high group, it was 16.8 months (95% CI, 4.4-NR; 

= .03). Median OS was 29.9 months (95% CI, 20.8-NR) and 18.2 months (95% CI, 11.7-NR) for the BMI low and BMI-high groups, respectively (

Having BMI of 25 kg/mq2 or more was constituted as an independent risk factor for mortality at multivariate analysis, with a hazard ratio of 3.99 (95% CI, 1.2-13.2; 

 = .02). Other risk factors included age and number of metastatic sites. There was a non-significant tendency to progression in the BMI-high group at the same multivariate analysis, with a hazard ratio of 2.76 (95% CI, 0.9-8.3; 

The mean age in this study was 63.5 years (range, 34-83 years), and 65% of patients were women. Former or never smokers made up 59% and 67% had 3 or more metastatic sites at the start of treatment.

In 2019, a separate retrospective trial looked at low 

 in patients with NSCLC who were treated with an EGFR TKI.

 These investigators found that pretreatment of patients with underweight BMI, or BMI of less than 18.5 kg/mq2, was a significant prognostic factor for poor PFS and OS of EGFR TKI treatment. The median PFS was 9.1 versus 14.8 months for those with underweight BMI (n = 33) and those with BMI of 18.5 kg/mq2 or more (n = 134), respectively (HR, 1.72; 95% CI, 1.11-2.67; 

= .03). The median OS was 26.0 compared with 32.3 months (HR, 1.70; 95% CI, 1.03-2.81; 

“In our experience, a BMI ≥25 kg/mq2 negatively influenced survival outcomes of 2nd-line osimertinib' treated NSCLC patients. More comprehensive studies are warranted to confirm these findings,” the investigators of the osimertinib analysis wrote in their conclusion.

1. De Giglio A, Di Federico A, Donati G, et al. The prognostic role of body-mass index (BMI) for advanced EGFR positive non-small cell lung cancer (NSCLC) patients treated with osimertinib. 

2. Minami S, Ihara S, Nishimatsu K, Komuta K. Low body mass index is an independent prognostic factor in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitor. 

In a retrospective analysis of patients with advanced non–small cell lung cancer and EGFR mutations treated with osimertinib, investigators found that body mass index of 25 kg/mq2 or more had a negative impact on survival outcomes.

High BMI Negatively Impacts Survival Outcomes With Osimertinib in EGFR+ NSCLC

A phase 2 trial of tislelizumab (BGB-A317) and another trial of Tumor Treating Fields (TTFields) accompanied by sorafenib (Nexavar) are filling unmet needs in advanced hepatocellular carcinoma (HCC), although more data are still needed in this space according to a discussion at the 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

Up until recently, the HCC landscape has been dominated by tyrosine kinase inhibitors. The first-line standard of atezolizumab (Tecentrig) and bevacizumab (Avastin) has been available since 2020 after demonstrating a 6.9-month progression-free survival (PFS), 19.2-month overall survival (OS), and 30% overall response rate (ORR). However, there is still uncertainty for using this therapy in the second or later line settings.

Additionally, there is a need for predictive markers to help guide the selection and sequencing of therapy, and for innovative options to overcome primary and secondary resistance to treatment.

“Tislelizumab is an active and safe investigational PD-1 antibody, in second and third line, comparable to other PD-1 agents,” Chris Verslype, MD, PhD, a digestive oncologist at the University Hospitals Leuven, Belgium, said in his presentation. The global, single-arm, phase 2 RATIONALE 208 study (NCT03419897) of the investigational agent tislelizumab at 200 mg intravenously every 3 weeks was evaluated in 249 patients with previously treated advanced HCC.

This trial had a 13.3% ORR, a PFS of 2.7, and an OS of 13.2 months. Patients number of prior lines of therapy did not affect the results. The treatment-related adverse events of grade 3 or more occurred in 14.5% of patients, and 4.8% discontinued treatment.

In this group of patients, 80% had metastatic disease, 36% had non-viral etiology, and 90% had Barcelona-Clinic Liver Cancer (BCLC) stage C. They could not have prior PD-1 or PD-L1 inhibitors.

Verslype compared these data with the phase 3 KEYNOTE-240 trial (NCT02702401) of pembrolizumab (Keytruda) versus placebo in 413 patients with pretreated advanced HCC, randomized 2:1. Seventy percent had metastatic disease, 80% had BCLC stage C, 58.6% had non-viral etiology, and 87% had progressive disease after receiving sorafenib. The results of this trial showed an 18.3% ORR, 3-month PFS, and 13.9-month OS. Grade 3 or more events of interest occurred in 7.2%.

The results from RATIONALE-208 and KEYNOTE-240 are comparable. Currently, there is a phase 3 trial of tislelizumab versus sorafenib in the first line setting for patients with unresectable HCC, though they are unlikely to yield clinically relevant results, according to Verslype’s discussion.

Subsequently, Verslype went over the phase 2 HEPANOVA trial (NCT03606590) of TTFields at 150 kHz for 18 or more hours a day plus daily sorafenib at 400 mg twice daily. The 27 patients on this trial were diagnosed with advanced HCC by biopsy or imaging plus alpha-fetoprotein, had BCLC stage 0-C, 5 to 8 Child-Pugh score, and could not receive surgery or local therapy.

In this trial, the ORR was 9.5%, the PFS was 5.8 months, and the OS rate at 1 year was 30%. There were 67% of patients with grade 1 or 2 TTFields-related skin toxicity, and 1 patient had grade 3 toxicity.

“For TTFields, there are no new safety concerns. [These are the] first good data in HCC, but more data are needed to appreciate the efficacy of TTFields in advanced HCC,” Verslype said.

Treatment for this trial started 7 days or less after enrollment, and TTFields start more or less than 7 days from starting sorafenib. Follow-ups occurred every 4 weeks and CT/MRI scans were scheduled for every 12 weeks. TTFields and follow-ups continued until progressive disease per RECIST. Follow-up visits after patients experienced progressive disease were 30 days after discontinuation. Survival follow-ups were every 8 weeks until death. Verslype also noted that there were 78% of patients with BCLC stage C, 51% with Child-Pugh B, and 22% with an ECOG performance status of 2 recently.

“Updated results from the IMbrave150 [NCT03434379] study evaluating atezolizumab/bevacizumab versus sorafenib [showed] that you can have with sorafenib…11% ORR and even a very high overall survival at 1 year,” Verslype explained during his presentation. “So in my opinion, recent studies with sorafenib as the control have shown better results than historical controls used in [HEPANOVA]. Is this really showing more efficacy than sorafenib? I doubt it.”

Verslype C. Discussion O-1, O-16. Slides presented at: 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; virtual. LBA-2. doi:

A phase 2 trial of tislelizumab and another trial of Tumor Treating Fields accompanied by sorafenib are filling unmet needs in advanced hepatocellular carcinoma, although more data are still needed in this space.

Dylann Cohn-Emery | Authors

Articles

FDA Recommends Including Patients on Trials Regardless of Prior Therapies in the Non-Curative Setting

HER2+ Status at Diagnosis in Patients With mBC Shows More Favorable PFS Than HER2-Negative Status

High BMI Negatively Impacts Survival Outcomes With Osimertinib in EGFR+ NSCLC

Phase 2 Trials Currently Filling Unmet Needs in Advanced HCC