Dylann Cohn-Emery

OneOncology, an oncologist network for community-based physicians and partner of independent oncology practices, announced the creation of OneOncology Research Network (OneR); this separate subsidiary is a national non-exclusive clinical trial site management organization, according to a press release.

The mission of OneR is to enhance research programs of participating community oncology practices through operational, regulatory, and research support services to help improve multicenter clinical trials.

“OneR is a community oncology network designed for and built by community oncology practices,” Lee Schwartzberg, MD, chief medical officer at OneOncology and medical director at West Cancer Center, said in a statement. “Our north star is improving the lives of everyone with cancer which is fundamentally dependent on advancing the science of oncology treatments. We look forward to working with practices and sponsors who want to expand diverse patient access to precision oncology and other high-quality cancer clinical trials through our portfolio of therapeutic and observational studies.”

Due to the importance of clinical trials for finding new and better standards of care for precision oncology, OneR will aid community practices by expanding their access to more innovative treatments for patients. While doing so, they will provide access to clinical trial sponsors to the broad population of patients treated at these community cancer centers throughout their cancer journey, as opposed to the episodic method more commonly taken at research-based academic centers. The clinical trials at community-based facilities will deliver more diversity in clinical trials in terms of geography, socioeconomics, disease status, gender, and ethnicity.

“With too many of our patients disproportionately impacted by health disparities, we believe that by providing community oncology practices with enhanced operational efficiencies we can ensure that more patients will benefit from the groundbreaking clinical trials,” Axel Grothey, MD, medical director of OneR and director of GI Cancer Research at West Cancer Center, said in a press release. “OneR will not only improve patient access to cutting-edge care, it will also help to advance scientific discovery.”

OneR’s emphasis on precision oncology will deliver innovative trial designs to clinical trials throughout multiple tumor types based on precision oncology to oncology practices working with them. This would include designs such as basket trials to see how well a novel therapy works in patients with different types of cancer with the same biomarkers or mutations, and umbrella trials for patients with one kind of cancer to receive a therapy based on their cancers molecular profile.

Since oncology practices continue to invest in clinical trial infrastructure, OneR will support partnered practices ability to increase participation in these trials with clinical trial matching technology, regulatory submissions, and by centralizing business functions. At the same time, they will ensure practices are able to maintain their flexibility to participate in other clinical trial initiatives. OneR is non-exclusive, so participating centers can be a part of other clinical trial programs as well.

1. OneOncology research network will enhance practices’ high-quality clinical trials programs while improving patients’ access to innovative oncology therapies. News release. OneOncology. October 19, 2020. Accessed October 22, 2020. 

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OneOncology announced the creation of OneOncology Research Network, which is a national non-exclusive clinical trial site management organization.

OneOncology Creates Program to Enhance Clinical Trials at Participating Community Practices

In a phase 2 trial (NCT03414034), onvansertib, a polo-like kinase 1 (PLK1) inhibitor, combined with abiraterone acetate (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have early abiraterone resistance, demonstrated a decent safety profile across 3 dosing schedules and efficacy in the evaluable arms.

“PLK1 is a regulator of the G2/M checkpoint and onvansertib is a highly selective and short half-life inhibitor of PLK1. So, interestingly, looking at preclinical cell lines and xenograft models, there appears to be a synergy between PLK1 inhibition and abiraterone,” David J. Einstein, MD, said in his presentation of the study authors’ poster during the 27th Annual Prostate Cancer Foundation Virtual Scientific Retreat. “That does not seem to be dependent on AR [androgen receptor] effects, so enzalutamide [Xtandi] does not recapitulate that synergy. We do see this synergy in AR-negative prostate lines and even non-prostate cancer cell lines.”

This combination achieved its primary end point of prostate specific antigen (PSA) stabilization in 8 (31%) of the evaluable patients across arms A and B (n = 26) in a preliminary evaluation of efficacy. Stable disease was observed in 14 (54%) patients at 12 weeks and durable response of over 7 months was seen in 8 (31%) patients.

Of the 8 patients with AR alterations associated with abiraterone resistance, 3 achieved disease control and 4 had stable disease. The AR mechanisms of resistance to abiraterone on this study consisted of AR-V7, the AR T878A mutation, and amplification of AR.

Additionally, onvansertib plus abiraterone induced circulating tumor cell (CTC) conversion from unfavorable to favorable, which also correlated with durable response in patients. Unfavorable CTC count was defined as 5 or more CTCs/7.5 mL of blood and favorable was less than 5 CTCs/7.5 mL of blood. The CTC count, which is a prognostic factor for survival in this population, was unfavorable in 27 (73%) patients at baseline. Of the 10 patients re-evaluated at 12 weeks, 5 had a CTC decrease of 80% or more and 4 had converted from unfavorable to favorable, which included 3 with no detectable CTCs.

For all 3 arms of the trial, there was a safety lead-in; arm A (n = 24) at 24 mg/m2 of onvansertib on days 1 through 5 of a 21-day cycle; arm B (n = 32) at 18 mg/m2 on days 1 through 5 of a 14-day cycle; and arm C (n = 32) at 12 mg/m2 on days 1 through 14 of a 21-day cycle. Treatment was given for 12 weeks, or 4 cycles in arm A and C and 6 cycles in arm B.

The most frequent grade 3/4 adverse events were hematologic—which was expected due to the mechanism of action of onvansertib—such as anemia, neutropenia, thrombocytopenia, and white blood cell decrease. These events were reversible and managed with dose delay, dose reduction, and/or growth factor support.

Investigators identified a synergistic gene signature, which was mostly made up of mitosis-related genes, that is enriched in patients with a basal molecular subtype compared with other subtypes (

<.001). They suggested that patients with this subtype may have a greater likelihood of response to the combination.

Patients with mCRPC on this trial had initial signs of abiraterone resistance of 2 rising PSAs¾1 rise of 0.3 ng/mL or more separated by 1 week. Patients were not considered eligible if they had prior treatment with enzalutamide or apalutamide (Erleada); if they had rapidly progressing disease; or significant symptoms related to disease progression.

Disease control was evaluated as PSA decline or stabilization¾defined as PSA rise of less than 25% over baseline¾after 12 weeks of treatment with the combination was the primary end point of the trial. The secondary end points were radiographic response per RECIST v1.1, time to PSA progression, and time to radiographic response. The investigators were also looking at CTCs and circulating tumor DNA to identify response biomarkers.

For baseline characteristics, 39 patients total were included. The median age was 72 years old (range, 54-87) and there were 5 patients who were not white. Most had an ECOG performance status of 0 (87%) and the rest had a status of 1. Nine (23%) patients had AR-V7 at baseline. The median CTC count/mL of blood was 2.2 at baseline (range, 0-87) and the median baseline PSA was 12.5 ng/mL (range, 0.6-224).

“In sum, onvansertib plus abiraterone seemed to be safe and demonstrated some preliminary efficacy data with about 30% of patients achieving disease control 3 months into therapy and some patients having durable stable disease, especially in association with decreases in CTC,” concluded Einstein, instructor of medicine at Harvard Medical School and attending physician at the Beth Israel Deaconess Medical Center. “We’ll be doing some more work looking at predictors of response and trying to clarify the mechanism of action, which seems relevant to mitosis.”

Einstein DJ, Choudhury A, Saylor P, et al. A phase 2 study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with abiraterone in patients with abiraterone (Abi)-resistant metastatic castration-resistant prostate cancer (mCRPC). Presented at: 27th Annual Prostate Cancer Foundation Virtual Scientific Retreat; October 20-23, 2020; Virtual. https://bit.ly/3dQbTnW

In a phase 2 trial, onvansertib, a polo-like kinase 1 inhibitor, combined with abiraterone acetate in patients with metastatic castration-resistant prostate cancer who have early abiraterone resistance, demonstrated a decent safety profile across 3 dosing schedules and efficacy in the evaluable arms.

PLK1 Inhibitor, Abiraterone Combo Shows Preliminary Efficacy and Safety in mCRPC

few years, investigators in the breast cancer field have tried to find new ways to treat triple-negative breast cancer (TNBC) to produce longer survival durations and higher response rates. To do so, they have performed investigations into genomic pathways to target specific characteristics of a patient’s tumor for better results with treatments, such as PARP inhibitors and chemotherapies used in different sequences.

In a presentation at the 2020 Lynn Sage Breast Cancer Symposium, Virginia G. Kaklamani, MD, DSc, reviewed the current genomic tools in the TNBC landscape that predict response to targeted treatments, including 

 mutations, and homologous recombination deficiency (HRD).

“AKT can be activated by loss-offunction mutations, gain-of-function mutations, and so forth,” Kaklamani, the leader of the Breast Cancer Program at the University of Texas Health San Antonio MD Anderson Cancer Center, said. “AKT is an extremely important molecule in this PI3k pathway…the mTOR/PI3K/AKT pathway is being used [for] drugs such as AKT inhibitors to treat even TNBC.”

The PI3K/AKT pathway is one of the most frequently altered pathways in breast cancer and is key for the survival and growth of tumors. The agent ipatasertib selectively targets AKT mutations and was used in the phase 2 LOTUS trial (NCT02162719) for 124 patients with measurable locally advanced or metastatic TNBC. These patients had no prior systemic therapy for advanced and/or metastatic disease and had received no chemotherapy for at least 6 months.

Patients were randomized to ipatasertib at 400 mg a day on days 1 to 21 in combination with paclitaxel at 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle versus paclitaxel and placebo dosed in a similar manner. The coprimary end points were progression-free survival (PFS) in the intention-to-treat (ITT) population and 

In the ITT group, the median PFS was 6.2 months with ipatasertib and 4.9 months with placebo (stratified HR, 0.60; 95% CI, 0.37-0.98). The 42 patients with 

-altered tumors by FoundationOne next-generation sequence testing had a median PFS of 9.0 months and 4.9 months with ipatasertib plus placebo, respectively (unstratified HR, 0.44; 95% CI, 0.20-0.99).

In the ITT group, the median PFS was 6.2 months with ipatasertib and 4.9 months with placebo (stratif ied HR, 0.60; 95% CI, 0.37-0.98). The 42 patients with PIK3CA/AKT1/PTEN-altered tumors by FoundationOne next-generation sequence testing had a median PFS of 9.0 months and 4.9 months with ipatasertib plus placebo, respectively (unstratified HR, 0.44; 95% CI, 0.20-0.99). 

“Based on that trial, ipatasertib is now being looked at in phase 3 trials in TNBC,” Kaklamani said. This includes an ongoing phase 3 clinical trial (NCT04177108) of the drug in combination with atezolizumab (Tecentriq) for 

locally advanced or metastatic triple-negative disease.

In a similar design, the phase 2 PAKT study (NCT02423603) also looked at the 

-altered population as a secondary end point of their trial. This trial investigated oral capivasertib at 400 mg twice daily on days 2 through 5, 9 through 12, and 16 through 19, plus paclitaxel at 90 mg/m

 intravenously on days 1, 8, and 15; each cycle lasted 4 weeks. This was compared with paclitaxel and placebo. There were 140 patients with TNBC randomized 1:1 for the primary end point of investigator-assessed PFS in the ITT population.

The PIK3CA/AKT1/PTEN-altered group (n = 28) showed significant improvement in PFS with a median of 9.3 months for those receiving capivasertib versus 3.7 months for those receiving placebo (HR, 0.30; 95% CI, 0.11-0.79; 2-sided 

 = .01). However, in patients who did not have altered tumors, the median PFS was 5.9 and 4.2 months, respectively, according to results published in 2020 (HR, 0.74; 95% CI, 0.50-1.08; 1-sided 

“This drug as well is being looked at in phase 3 trials as we speak,” Kaklamani added. “…PIK3CA mutations are being used now to predict response to a PI3K inhibitor and this is standard of care now for our clinic.”

Another way to look at the TNBC setting is through the predictive biomarker of HRD. “HRD assays can predict not 

only sensitivity to platinum [chemotherapy], but potentially sensitivity to PARP inhibitors,” Kaklamani said.

A pooled analysis of 5 phase 2 trials looking at patients with TNBC treated with neoadjuvant platinum-based chemotherapy showed that HRD can predict pathologic complete response (pCR) in these patients. In the analysis, patients with HRD tumors were more likely to achieve a pCR than those with nondeficient tumors at 44% versus 8%, respectively (

“HRD is predictive of chemotherapy benefit. All of these trials included a platinum [therapy]…. I think the bottom line from this is that when we use the HRD score, we can help predict chemotherapy benefit in the neoadjuvant setting,” Kaklamani said.

Kaklamani examined one of the trials (NCT01372579) to see if carboplatin and eribulin was efficacious in these patients. The investigators were “able to show this treatment had a 43.3% rate of residual cancer burden, which is relatively impressive for 4 cycles of chemotherapy that are also not anthracycline based,” she said. They were also looking at the residual cancer burden in patients with HRD, and those who had higher HRD scores had a higher rate of pCR at 75%.

More recently, in a phase 2 trial of olaparib monotherapy (NCT03344965), patients with germline mutations were put into cohort 1 and patients with somatic mutations were put into cohort 2. Responses were seen in 5 out of 10 patients with TNBC included in the trial. The overall response rate was 33% in cohort 1 and 31% in cohort 2.

, there is some evidence that giving a PARP inhibitor may help with responses in a third of the patients.”

-like will have high HRD scores, according to Kaklamani. The primary end point of the SWOG S1416 trial (NCT02595905) was PFS in 3 prespecified groups: germline 

Patients with metastatic and/or locoregionally recurrent TNBC or germline 

mutationassociated HER2-negative metastatic breast cancer were tested for mutations after 1:1 randomization. To be in the 

-like group, they had to have an HRD genomic instability score of 42 or more, a somatic 

 promoter methylation, or mutations in germline homologous recombination repair genes besides 

Investigators assessed the efficacy of oral veliparib at 300 mg twice a day on days 1 through 14 plus cisplatin at 75 mg/m

 on day 1 of a 21-day cycle compared with cisplatin and placebo.

-like groups, there was no statistically significant difference between veliparib and placebo for the median PFS or overall survival. Conversely, in the 

-like group, patients experienced a better median PFS with veliparib at 5.9 months versus 4.2 months with placebo, which reached statistical significance (HR, 0.53; 95% CI, 0.340.83; 

The overall response rate for this group (n = 83) was 45% with veliparib and 33% with placebo, “showing that [the] veliparib and cisplatin combination can be effective in 

-like tumors…. We don’t want to be using a PARP inhibitor in non–

-mutated patients,” Kaklamani explained.

Upcoming in this setting is the phase 2 PERSEVERE study (NCT02101385) for patients with TNBC and residual disease after neoadjuvant therapy to analyze the use of genomically directed therapy. Patients will be separated according to whether they are positive or negative for genomically directed mutations through circulating tumor DNA (ctDNA). If their ctDNA comes back negative, they will be given physician’s choice of treatment. If it comes back positive but there is no genomic target, they will be given the standard of care.

If a patient’s ctDNA comes back positive and they have a genomically directed pathway, they will be given 1 of 4 therapies. These include a PARP inhibitor for the DNA repair pathways, atezolizumab for alterations in the immunotherapy pathways, ipatasertib for the PI3K/ AKT/mTOR pathways, and a PARP inhibitor plus atezolizumab for the DNA repair plus immunotherapy pathways. All of these therapies are in combination with capecitabine.

“This tells [us] that, if this trial is successful, we will be able to use the patient’s tumor’s 

mutations to target their treatment instead of giving every single patient the exact same chemotherapy, which is what we’ve been doing so far,” Kaklamani said.

1. Kaklamani V. Genomic tools that predict response in breast cancer. Presented at: 22nd Annual Lynn Sage Breast Cancer Symposium; September 10-12, 2020; Virtual. Accessed September 23, 2020. https:// bit.ly/2SgTtT6

2. Kim SB, Dent R, Im SA, et al; LOTUS investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. 

. 2017;18(10):1360-1372. doi:10.1016/S1470-2045(17)30450-3 

3. Schmid P, Abraham J, Chan S, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple- negative breast cancer: the PAKT trial. 

. 2020;38(5):423-433. doi:10.1200/JCO.19.00368

4. Telli ML, McMillan A, Ford JM, et al. Homologous recombination def iciency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): a pooled analysis. 

s. 2016;76(suppl 4):P3-07-12. doi:10.1158/1538-7445.SABCS15-P3-07-12 

5. Kaklamani VG, Jeruss JS, Hughes E, et al. Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). 

t. 2015;151(3):629638. doi:10.1007/s10549-015-3435-y 

6. Tung NM, Robson ME, Ventz S, et al; Translational Breast Cancer Research Consortium. TBCRC 048: a phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded). 

l. 2020;38(suppl 15):1002. doi:10.1200/JCO.2020.38.15_ suppl.1002 

7. Sharma P, Rodler E, Barlow WE, et al. Results of a phase II randomized trial of cisplatin +/- veliparib in metastatic triple-negative breast cancer (TNBC) and/or germline BRCA-associated breast cancer (SWOG S1416). 

l. 2020;38(suppl 15):1001. doi:10.1200/JCO.2020.38.15_ suppl.1001

In a presentation at the 2020 Lynn Sage Breast Cancer Symposium, Virginia G. Kaklamani, MD, DSc, reviewed the current genomic tools in the triple negative breast cancer landscape that predict response to targeted treatments.

Investigators Tailor TNBC Therapy Using Genomic Alterations

The creation of the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9), a novel gene-editing technology used in oncology and other areas of scientific research was the antecedent for Emmanuelle Charpentier, PhD, a professor at the Max Planck Unit for the Science of Pathogens in Germany, and Jennifer A. Doudna, PhD, a professor at the University of California, Berkeley, being awarded the 2020 Nobel Prize in Chemistry.

CRISPR is a technology can alter the DNA in human cells through gene editing, which in the case of cancer could detect specific targets like RNA from cancer cells and DNA from cancer-causing viruses.

“With the development of the CRISPR/Cas9 system, Charpentier and Doudna established a groundbreaking genome-editing mechanism that has contributed to monumental progress in molecular biology and genetics and is advancing our understanding of tumor initiation and progression,” Margaret Foti, PhD, MD (hc), chief executive officer of the American Association of Cancer Research (AACR), said in a statement. “This year’s Nobel Prize in Chemistry is richly deserved, and we offer our deepest congratulations to these esteemed scientists.”

The technology is considered easy to use compared with other gene-editing tolls and is customizable. It can be used to edit almost any segment of DNA in the human genome by adding or deleted sequences and is considered more precise than other DNA-editing tools.

Oncologists are trying to use this technology with a patient-first approach at community cancer centers like Christiana Care. The process for using CRISPR at their institution 

, and how this technology could further help patients in different cancer settings such as lymphoma and T cell leukemia. Clinical trials are also underway to investigate the use of CRISPR in different cancer types such as metastatic non-small cell lung cancer (NCT02793856).

Charpentier and Doudna were selected by their colleagues to be fellows at the AACR Academy in 2017. Those a part of the AACR Academy aim to use research, education, communication, and collaboration to prevent and cure all cancers. Being selected is also meant to recognize and honor scientists who have contributed significant innovation and progress in the cancer setting.

Doudna most recently received awards in 2018, including the Microbiology Society Prize Medal Winner, American Cancer Society Medal of Honor, Kavli Prize in Nanoscience, V de Vida Award, Croonian Medal, AACR-Irving Weinstein Foundation Distinguished Lectureship, and the NAS Award in Chemical Sciences. Charpentier has most recently won awards in 2017 such as the Albany Medical Center Prize in Medicine and Biomedical Research, Albany, New York, Elected Foreign Associate, National Academy of Sciences, and the Japan Prize. Both women have over 40 awards between them spanning back to 1999.

“We celebrate the spectacular achievements of these scientists, whose work is being applied to all aspects of cancer research for the benefit of cancer patients worldwide,” Foti said in a press release.

1. AACR congratulates Emmanuelle Charpentier and Jennifer A. Doudna on the 2020 Nobel Prize in Chemistry. New release. Published October 7, 2020. Accessed October 9, 2020. https://bit.ly/34IAI0z

2. How CRISPR is changing cancer research and treatment. News release. Published July 27, 2020. Accessed October 9, 2020. https://bit.ly/2If7wa7

The creation of the CRISPR-Cas9, a novel gene-editing technology used in oncology and other areas of scientific research was the antecedent for Emmanuelle Charpentier, PhD, and Jennifer A. Doudna, PhD, being awarded the 2020 Nobel Prize in Chemistry.

Author | Dylann Cohn-Emery

Articles

OneOncology Creates Program to Enhance Clinical Trials at Participating Community Practices

PLK1 Inhibitor, Abiraterone Combo Shows Preliminary Efficacy and Safety in mCRPC

Investigators Tailor TNBC Therapy Using Genomic Alterations

Nobel Prize in Chemistry Goes to Developers of Genome Editing System CRISPR