Dylann Cohn-Emery

An exploratory analysis of trastuzumab emtansine (T-DM1) demonstrated activity and tolerability in patients with HER2-positive locally advanced or metastatic breast cancer who have brain metastases participating in the prospective KAMILLA trial (NCT01702571).

“Despite advances in the treatment of HER2-positive metastatic breast cancer, a notable unmet need remains for patients who also have brain metastases,” the investigators wrote in their conclusion. “This exploratory subgroup analysis of KAMILLA represents the largest reported cohort of patients with HER2-positive metastatic breast cancer and brain metastases treated with T-DM1 in a prospective setting. We observed clinically meaningful antitumor activity in patients with and without prior radiotherapy, suggesting that T-DM1 is active in this population and warrants further exploration.”

For the analysis, investigators looked at cohort 1 of this single-arm phase 3b study, where 398 out of 2002 patients had brain metastases at baseline. Among the 398 patients, there was a median progression-free survival of 5.5 months (95% CI, 5.3-5.6 months) and a median overall survival of 18.9 months (95% CI, 17.1-21.3 months).

In 126 patients with measurable brain metastases, there was a best overall response rate of 21.4% (95% CI, 14.6%-29.6%) and a clinical benefit rate of 42.9% (95% CI, 34.1%-52.0%). This group had 3 complete responses, 24 partial responses, and 27 patients with stable disease lasting 6 months or more.

There was a reduction in the sum of the major diameters of brain metastases of 30% or more for 42.9% (95% CI, 34.1%-52.0%) of patients with brain metastases. For 67 patients without prior radiotherapy to their brain metastases, 49.3% (95% CI, 36.9%-61.8%) had a reduction of 30% or more.

Patients with and without brain metastases had a similar adverse event profile, but nervous system toxicities in patients with baseline metastases were more common. There were 701 (43.7%) compared with 208 (52.3%) with nervous system adverse events in the group of patients with baseline brain metastases and those without, respectively.

In KAMILLA, patients received T-DM1 at 3.6 mg/kg intravenously every 3 weeks until they experienced unacceptable toxicity, withdrew consent, or had disease progression. The median treatment duration with T-DM1 was 4.9 months (range, 0-44 months) in patients with brain metastases.

This post-hoc, exploratory analysis investigated tumor response and clinical outcomes with those with baseline brain metastases. The primary end points included the best overall response rate and clinical benefit rate by RECIST v1.1 criteria, progression-free survival, overall survival, and safety.

The median age of patients with brain metastases at baseline was 52 years old (range, 28-83). They had an ECOG performance status of 0 (48.2%), 1 (43.7), or 2 (8.0%). A majority of these patients were estrogen receptor-negative and/or progesterone receptor-positive (61.8) or estrogen receptor-negative and/or progesterone receptor-negative (37.7). Most of these patients had 1 (23.4%) or 2 (22.9%) lines of therapy for metastatic disease.

Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. 

. Published online July 4, 2020. Accessed July 9, 2020. doi:10.1016/j.annonc.2020.06.020

Articles

An exploratory analysis of trastuzumab emtansine demonstrated activity and tolerability in patients with HER2-positive locally advanced or metastatic breast cancer  who have brain metastases participating in the prospective KAMILLA trial.

T-DM1 Shows Activity in HER2+ Metastatic Breast Cancer and Brain Metastases

The last patient with advanced hepatocellular carcinoma (HCC) was enrolled on the phase 2 HEPANOVA trial (NCT03606590), which is investigating the combination of Tumor Treating Fields (TTFields) and sorafenib (Nexavar). The combination showed safety and tolerability for patients in an interim analysis.

This prospective, single-arm pilot trial demonstrated no serious adverse events (AEs) that were unanticipated at the time of the interim analysis in the first 9 patients. Most of the toxicities were expected and associated with HCC or chemotherapy, and the most common AE at the time of the analysis was TTFields-related dermatitis, which was expected.

For all 9 patients, the total treatment duration of TTFields was 29.1 months. Among these patients, 6 (66.7%) experienced severe grade 3/4 AEs and 3 (33.3%) experienced serious AEs, but none of these events were related to TTFields. The only TTFields-related AE was mild-moderate skin toxicity, which was reported in 7 (78%) of the patients. There was a median treatment duration of 2 months with sorafenib and 3 months with TTFields.

Preclinical studies showed that 150kHz of TTFields reduced HepG2 and Huh7D12 cell counts from 53% to 64% and clonogenic potential of about 70%. In an 

 study, TTFields combined with sorafenib led to a significant reduction in the number of HepG2 and Huh-7D12 cells (

<.001) compared with TTFields alone and sorafenib alone.

 Another study demonstrated a reduced viability, clonogenicity, and increased apoptosis and autophagy 

 and a significant reduction in tumor volume 

“TTFields therapy has demonstrated efficacy in 

 models of HCC,” Asaf Danziger,chief executive officer, Novocure, said in a statement. “We believe that TTFields’ mechanism of action is broadly applicable to solid tumor cancers. We look forward to seeing results from the HEPANOVA trial and further exploring the potential of TTFields as a treatment for advanced liver cancer.”

Now that the last patient is enrolled in the study as of July 7, the final data collection date is 6 months after. The primary end point is overall response rate and the secondary end points include overall survival rate, progression-free survival rate, and distant metastases free survival rate at 1 year, as well as the in-field control rate.

The 25 patients are receiving TTFields at 150 kHz concomitant with sorafenib 400 mg twice daily. The sample size of this trial was based on the ability to detect an overall response rate of 20% in patients given TTFields versus the 4.5% overall response rate calculated from historical controls.

All of the patients had advanced HCC and were ineligible for surgical resection or local treatments. The median age was 70 years old in the interim analysis and all the patients were male. Three patients had an ECOG performance score of 0. There was a median time from diagnosis of 9 months (range, 0-56 months) and the median number of prior treatments was 2 (range, 0-6 treatments). There were 5 patients with Barcelona Clinic Liver Cancer stage B disease.

1. Novocure enrolls last patient in HEPANOVA trial testing tumor treating fields in combination with sorafenib in advanced liver cancer. News release. Novocure. Published July 7, 2020. Accessed July 9, 2020. https://bit.ly/3f9Xenc

2. Gkika E, Brunner T, Thimme R, Grosu A-L. CT186 - HEPANOVA: Interim safety analysis from a phase 2 study of Tumor Treating Fields (TTFields, 150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma (HCC) [Abstract]. In: Proceedings of the 111th Annual Meeting of the American Association for Cancer Research; 2020 June 22-24. Philadelphia (PA): AACR; 2020. Abstract nr CT186.

3. Gotlib K, Zeevi E, Schniederman RS, et al. The combined treatment of 150 kHz Tumor Treating Fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res. 2018;78(13 Suppl):Abstract nr 1865.

4. Davidi S, Tempel-Brami C, Munster M, et al. In vitro and in vivo efficacy and safety of tumor treating fields (TTFields) and sorafenib combination in hepatocellular carcinoma.

. 2020;38(suppl 4):551. doi:10.1200/JCO.2020.38.4_suppl.551

The last patient with advanced hepatocellular carcinoma was enrolled on the phase 2 HEPANOVA trial, which is investigating the combination of Tumor Treating Fields and sorafenib. The combination showed safety and tolerability for patients in an interim analysis.

HEPANOVA Trial Update: Final Patient With HCC Enrolled to Receive TTFields/Sorafenib

The 2020 Oncology Alliance (COA) Practice Impact Report, released on April 24 during the Community Oncology Conference, showed a significant increase in community oncology practices merging and/or being acquired by nonhospital practices or corporate entities. The report also touched on pandemic-related concerns for community practices.

Since 2008, 1748 community oncology clinics and/or practices have closed, been acquired by hospitals, undergone corporate mergers, or reported financial difficulties. Broken down, that includes 435 individual clinic treatment sites that closed; 348 practices, usually made up of multiple clinics, that reported financial difficulties from issues with bills and/or struggling to stay open; and 40 practices that sent their patients on Medicare elsewhere for chemotherapy.

Furthermore, 722 practices were acquired by a hospital or (less likely) entered into a contractual professional service agreement binding that practice to a hospital, and 203 merged with another community oncology practice and/or were acquired by a corporate entity. 

On a state-by-state basis, the largest number of practice closures was in Florida, with 47; Texas, 44; and California and Michigan, 36 each; and Tennessee, 20.

The number of practices merging with or being acquired by another community oncology practice and/or corporate entity rose by 20.8% compared with the number in the 2018 COA Practice Impact Report. This year’s authors speculate that the change is because practices want protection from hospital merger pressures. These practices received financial incentives through the 340B Drug Discount Program and higher payments to hospitals for cancer care services, also the reason for a 9.7% increase in practices acquired by hospitals from 2018 to 2020.

“Over the last 12 years, an average of 9 practices per month have closed, been acquired by a hospital, or merged. These are troubling trends and dangerous for patients battling cancer,” Michael Diaz, MD, president of COA and director of patient advocacy at Florida Cancer Specialists & Research Institute, said in a statement.

According to the report, early data show that the pandemic will significantly affect practices that already report a dramatic decrease in treatments, visits, and new patients. Although policy changes and government support are helping these practices stay open, uncertainty remains over whether hospitals will use unrestricted bailouts to drive growth after the crisis by pressuring more community oncology practices into acquisitions.

The COA Practice Impact Report tracks changes in the landscape of community cancer care in the United States through public and private data sources. The community oncology trends from national and state data are covered in a 12-year period in the 2020 report, from January 2008 to April 2020. This is the eighth report published by COA.

2020 Community Oncology Alliance Practice Impact Report. COA. April 24, 2020. Accessed April 28, 2020. https://bit.ly/3bo17SS

"Since 2008, 1748 community oncology clinics and/or practices have closed, been acquired  by hospitals, undergone  corporate mergers, or reported financial difficulties."

Community Practice Mergers and Acquisitions Rise Steeply Over 2  Years, COA Report Reveals

Taletrectinib (DS-6051b/AB-106) showed preliminary efficacy and manageable toxicities at the maximum tolerated dose (MTD) in a phase 1 trial of patients with advanced solid tumors.

“Taletrectinib is a promising oral tyrosine kinase inhibitor highly selective for 

,” Sai-Hong Ignatius Ou, MD, PhD, the corresponding author of the paper from University of California Irvine School of Medicine, said in a statement. “The drug had manageable toxicities at the MTD of 800 mg daily and showed preliminary efficacy in crizotinib-refractory ROS1 positive NSCLC patients.”

For 6 of the patients with non-small cell lung cancer (NSCLC) who were RECIST-evaluable, crizotinib (Xalkori)-refractory, and

-positive, there was a confirmed overall response rate of 33.3%. One patient with 

 differentiated thyroid cancer achieved a confirmed partial response of 27 months by the time of the data cutoff. The investigators identified an acquired taletrectinib-resistance mutation—a cabozantinib-sensitive 

There was a steady-state peak concentration and exposure for 46 patients enrolled in the trial, which was increased dose-dependently from 50 mg to 800 mg daily doses of taletrectinib. There was a 123% (90% CI, 104%-149%) ratio of the geometric mean of AUC024 between patients who were low-fat-diet-fed and those in a fasted state.

Two patients had dose-limiting toxicities of grade 3 transaminases increase. The most common treatment-related adverse events were nausea at 47.8%, diarrhea at 43.5%, and vomiting at 32.6%. There were pain score reductions observed in the 800 mg daily-dose cohort.

“We are honored to have our study selected for publication in 

. There is a significant unmet need for next generation tyrosine kinase inhibitors to overcome resistance that develops to existing agents like crizotinib, and we are highly focused on developing taletrectinib for both first, and second-line use in global markets,” Bing Yan, MD, MBA, chief medical officer and founder of AnHeart, said in a press release. “We are steadily making progress towards launching our Phase 2 trials [NCT04395677] in first-and second-line NSCLC patients with 

In this study, patients who were 18 years or older with neuroendocrine tumors, with tumor-induced pain, or tumors harboring 

rearrangements were eligible. There was accelerated titration followed by modified continuous reassessment method and escalation with overdose control used for these patients. The doses of taletrectinib ranged from 50 mg to 1200 mg once daily or 400 mg twice daily.

The primary end points of the trial were safety/tolerability and MTD determination. Secondary end points included food-effect pharmacokinetics and antitumor activity.

These data were supported by AnHeart Therapeutics, Co., Ltd., a clinical stage biopharmaceutical oncology company which is focused on developing novel agents for patients who are underserved in global markets.

1. Papadopoulos KP, Borazanci E, Shaw AT, et al. US phase 1 first-in-human study of taletrectinib (DS-6051b/AB-106), a ROS1/TRK inhibitor, in patients with advanced solid tumors. Clin Cancer Res. Published OnlineFirst June 26, 2020. doi:10.1158/1078-0432.CCR-20-1630

2. AnHeart Therapeutics Announces Acceptance of Taletrectinib Phase 1 Data for Publication in Clinical Cancer Research [press release]. GlobeNewswire. Published June 26, 2020. Accessed June 26, 2020. https://bit.ly/31k0Lv6

"Taletrectinib is a promising oral tyrosine kinase inhibitor highly selective for ROS1/NTRK mutations with potent activity against ROS1 resistance mutations like G2032R."

Author | Dylann Cohn-Emery

Articles

T-DM1 Shows Activity in HER2+ Metastatic Breast Cancer and Brain Metastases

HEPANOVA Trial Update: Final Patient With HCC Enrolled to Receive TTFields/Sorafenib

Community Practice Mergers and Acquisitions Rise Steeply Over 2 Years, COA Report Reveals

Taletrectinib Shows Preliminary Efficacy in Crizotinib-Refractory ROS1+ NSCLC