A stepped-wedge cluster randomized clinical trial published in 

 indicated that an intervention that delivered machine learning mortality predictions with behavioral nudges to oncology clinicians significantly increased the rate of serious illness conversations (SIC) among all patients, especially among those with high mortality risk who were targeted by the intervention.

Based on these findings, researchers suggested behavioral nudges combined with machine learning mortality predictions can effectively influence clinician behavior and may be applied more broadly to enhance care for patients nearing the end of life.

“Within and outside of cancer, this is one of the first real-time applications of a machine learning algorithm paired with a prompt to actually help influence clinicians to initiate these discussions in a timely manner, before something unfortunate may happen,” co-lead author Ravi B. Parikh, MD, an assistant professor of Medical Ethics and Health Policy and Medicine in the Perelman School of Medicine at the University of Pennsylvania and a staff physician at the Corporal Michael J. Crescenz VA Medical Center, said in a press release.

 “And it’s not just high-risk patients. It nearly doubled the number of conversations for patients who weren’t flagged—which tells us it’s eliciting a positive cultural change across the clinics to have more of these talks.”

The study was conducted across 20 weeks at 9 medical oncology clinics within a large academic health system in Pennsylvania, including 8 subspecialty oncology and 1 general oncology clinics. Clinicians at the 2 smallest subspecialty clinics were grouped together, which resulted in a total of 8 clinic groups randomly assigned to 4 intervention wedge periods.

The study sample consisted of a total of 78 clinicians and 14,607 patients. Interventions assessed in the study included weekly emails to oncology clinicians with SIC performance feedback and peer comparisons; a list of up to 6 high-risk patients (10% predicted risk of 180-day mortality) scheduled for the next week, estimated using a validated machine learning algorithm; and opt-out text message prompts to clinicians on a given patient’s appointment day to consider an SIC. Those included in the control group received usual care, consisting of weekly emails with cumulative SIC performance.

Across all patient encounters, SICs were conducted among 1.3% in the control group and 4.6% in the intervention group, which was deemed to be a significant difference (adjusted difference in percentage points, 3.3; 95% CI, 2.3-4.5; 

 < .001). Moreover, of 4124 high-risk patient encounters, SICs were conducted among 3.6% in the control group and 15.2% in the intervention group, which was also found to be a significant difference (adjusted difference in percentage points, 11.6; 95% CI, 8.2-12.5; 

“A key innovation of the present study was integrating behavioral economic principles into the [machine learning] based intervention, including peer comparison, performance feedback, and opt-out reminders, which have been used successfully in other clinical settings to change clinician behavior,” the authors noted. “Future implementation of artificial intelligence or [machine learning] tools in clinical practice should explore similar mechanisms of delivering predictions and integrating behavioral principles to maximally improve clinician and patient decision-making.”

Importantly though, this study was performed in a single academic health system, and the participants may not be representative of the general population of oncologists or patients with cancer. In addition, given that the study intervention consisted of several components, including a real-time prediction algorithm, a secure list of high-risk patients, peer comparisons, performance reports, and text messages, future work is necessary to assess the individual effects of each of these interventions.

“This is one of the first applications of combing behavioral nudges with machine learning methods in clinical care,” senior author Mitesh S. Patel, MD, director of the Penn Medicine Nudge Unit and an associate professor of Medicine in the Perelman School of Medicine at the University of Pennsylvania and a staff physician at the Corporal Michael J. Crescenz VA Medical Center, said in the release “There are many opportunities build upon this work and apply it to other aspects of cancer care and to other areas of medicine.”

1. Manz C, Parikh RB, Small DS, et al. Effect of Integrating Machine Learning Mortality Estimates With Behavioral Nudges to Clinicians on Serious Illness Conversations Among Patients With Cancer. 

2. Nudges Combined with Machine Learning Triples Advanced Care Conversations Among Patients with Cancer [news release]. Philadelphia. Published October 15, 2020. Accessed October 16, 2020. https://www.pennmedicine.org/news/news-releases/2020/october/nudges-combined-with-machine-learning-triples-advanced-care-conversations-among-patients-with-cancer

Articles

An intervention that delivered machine learning mortality predictions with behavioral nudges to oncology clinicians significantly increased the rate of serious illness conversations among all patients included in this study.

Machine Learning Intervention Triples Serious Illness Conversations Among Oncology Clinicians

The Fluorescent Light Activated Synthetic Hypericin (FLASH) study examining SGX301 (synthetic hypericin) to treat patients with cutaneous t-cell lymphoma (CTCL) improved responses for patients and maintained a tolerable safety profile, according to Soligenix.

The data suggests that SGX301 remained tolerable for patients as the lack of hypericin circulation in the blood stream after topical application to lesions and the use of visible light benefited the patients.

"Along with SGX301's rapid response time and safety profile, the patch and plaque data from the study are extremely compelling," Brian Poligone, MD, PhD, lead enrolling investigator in the FLASH study, said in a press release. "Current treatments for CTCL are generally less effective against plaques and deeper lesions, very similar to the problem observed in psoriasis.”

Cycle 3 of the study found that SGX301 treatment further improved response rates, with 49% of patients receiving the treatment for 18 weeks showing a 50% or greater reduction in their combined Composite Assessment of Index Lesion Score (CAILS). This number is compared favorably to 40% of patients showing the same reduction after 12 weeks of treatment in cycle 2 of the study (

More, continued analysis of cycles 1 and 2 of the study found that 12 weeks of treatment with SGX301 was equally effective on both patch ( 37%; 

< .0001) lesions when compared to the cycle 1 placebo responses.

“The ability of SGX301 to target both patches and thicker plaques in CTCL is an important feature for this therapy and, if approved, will be of benefit to patients, regardless of their presentation,” said Poligone. “These results are consistent with the positive findings highlighted in a recently reported case study of folliculotropic mycosis fungoides, a hard to treat variant of CTCL where lesions are associated with the hair follicles deep in the skin and more resistant to phototherapy."

Cycle 3 of the study was specifically designed as a compassionate use, optional, cycle in which patents had the option to continue SGX301 treatment for 6 more weeks. Of the total study cohort of 169 patients, 66% chose to continue treatment. Similar to the previous cycles before it, the findings in cycle 3 were statistically significant in regard to the response of individual lesions.

More, there was no synthetic hypericin detected in the blood stream of patients, which helped to minimize concerns for drug effects outside of the tumor area. Overall, the researchers report that the safety profile is tolerable, which sits in contrast with existing second-line and off-label therapies for CTCL.

“These results continue to strengthen our long-standing belief that SGX301 has the potential to be a valuable and life-changing therapy for patients suffering from CTCL, which is an orphan disease and area of unmet medical need," Christopher J. Schaber, PhD, president and chief executive officer of Soligenix, said in a press release. "With the study now concluding, we continue to thoroughly assess commercialization and/or partnership of SGX301 while in parallel preparing for filing the New Drug Application with FDA.”

Soligenix Announces Phase 3 FLASH Study Continues to Demonstrate Positive Benefits in Patients with Cutaneous T-Cell Lymphoma [news release]. Princeton, New Jersey. Published October 22, 2020. 

https://www.prnewswire.com/news-releases/soligenix-announces-phase-3-flash-study-continues-to-demonstrate-positive-benefits-in-patients-with-cutaneous-t-cell-lymphoma-301157831.html

Cycle 3 of the FLASH study reported that patients taking SGX301 to treat cutaneous t-cell lymphoma saw improved responses and maintained a positive safety profile.

SGX301 Demonstrates Positive Benefits for Cutaneous T-Cell Lymphoma 

, the Proceedings of the National Academy of Sciences of the United States of America, demonstrated for the first time that radiation remodels T-cell responses found within the tumors of patients with renal cell carcinoma (RCC), a form of kidney cancer that was previously thought to be radiation-resistant.

, senior author Jason Muhitch, PhD, assistant professor of Oncology in the Departments of Urology and Immunology at Roswell Park Comprehensive Cancer Center, discussed the study findings and how this research could possibly impact practice guidelines for this patient population moving forward.

: Can you explain the key highlights of the study?

Our team studied kidney tumors resected after radiation treatment to uncover how this therapy influences patient antitumor immune responses. Analysis of the intratumoral T-cells revealed that tumors treated with radiation had a more clonal T-cell repertoire compared to patient tumors that were only resected. By identifying the intratumoral T-cell clones through high-throughput sequencing, we revealed that these same clones were expanded 2 weeks after radiation in peripheral blood samples. Interestingly, these same tumor-enriched T-cell clones were contracted in peripheral blood samples taken 4 weeks after radiation.

What would you say are the implications of these study findings?

The observed phases of expansion and contraction in patient peripheral blood samples could indicate a window in which radiation promotes T-cell activation and expansion, which is restrained relatively quickly. These same T-cell clones may also be actively infiltrating the tumor and the observed changes in peripheral blood may represent a combination of these processes. To decipher the relative contributions of T-cell activation and infiltration to the observed changes in peripheral blood will clearly require additional studies.

How could these study findings change practice guidelines in the future?

There are dozens of open clinical trials evaluating the combination of radiation regimens with various forms of immunotherapy. As the field learns more about the mechanisms of action and biomarkers of immune-based treatments, we are likely to improve design and rationale to benefit patients. The study findings in kidney cancer patients at a specific radiation dose reveal that there may be a window of expansion that could be leveraged with certain types of immunotherapy, but additional work is required.

Are there any sort of planned next steps for the study?

Whether specific radiation doses heighten, or limit patient antitumor immune responses is a longstanding question in the field. Future studies will evaluate the influence of radiation dose and scheduling on patient antitumor immunity.

For patients who may not understand these findings, how would you explain the study findings in lay terms?

By studying the effects of radiation and immunotherapy on the immune cells of people treated for kidney cancer, we learned that we may be able to improve the effectiveness of this treatment combination through careful timing or sequencing of the treatments.

Chow J, Hoffend NC, Abrams SI, Schwaab T, Singh AK, Muhitch JB. Radiation induces dynamic changes to the T-cell repertoire in renal cell carcinoma patients. 

. doi: 10.1073/pnas.2001933117/-/DCSupplemental

Researchers demonstrated for the first time that radiation remodels T-cell responses found within the tumors of patients with renal cell carcinoma.

Study Finds Radiation Remodels T-Cell Responses in Patients with RCC

The second part of the phase 3 CASSIOPEIA trial produced positive topline results in its examination of daratumumab (Darzalex) monotherapy as maintenance treatment for patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT), according to an announcement by Genmab.

The study’s second part met its primary end point of improving progression free survival at a pre-planned interim analysis (HR, 0.53; 95% CI, 0.42-0.68; 

 < .0001), which resulted in a 47% reduction in the risk of disease progression or death for patients treated with the monotherapy.

“Following the positive data from the first part of the CASSIOPEIA study, we are very pleased to see this benefit,” said chief executive officer of Genmab, Jan van de Winkel, PhD, in a press release. “We are appreciative of the efforts of the IFM, of HOVON and of Janssen for their work on this study.”

The data was collected from 1085 newly diagnosed patients with previously untreated symptomatic multiple myeloma eligible for high dose chemotherapy and ASCT.

The first part of the study randomized the cohort of patients to receive induction and consolidation treatment with daratumumab combined with bortezomib, thalidomide and dexamethasone (VTd) or VTd alone, with a primary end point of the number of patients that achieved a stringent complete response (sCR).

More, part 1 of the study showed that D-VTd before and after ASCT improved depth of response and progression-free survival, while maintaining an acceptable safety profile. The researchers claim that this study is the first of its kind to show the “clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma.”

Then, for the second part of the research, the patients who achieved a response to the monotherapy underwent a second randomization to receive maintenance treatment of daratumumab or no further treatment.

The CASSIOPEIA trial is a randomized, open-label, multicenter phase 3 study being conducted by the French Intergroupe Francophone du Myelome (IFM) in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and Janssen Research & Development, LLC.

It was recommended that the results be unblinded following the results at a pre-planned interim analysis conducted by an Independent Data Monitoring Committee (IDMC). Janssen plans to submit the data to an upcoming medical conference and for publication in a peer reviewed journal.

Multiple myeloma is the third most common blood cancer in the United States. Approximately 26,000 people were expected to be diagnosed with the incurable blood cancer in the United States in 2018, with approximately 13,650 dying from the disease. The disease starts in the bone marrow and can cause symptoms such as bone problems, low blood counts, calcium elevation, kidney problems or infections.

1. Genmab Announces IFM, HOVON and Janssen Achieve Positive Topline Results in Second Part of Phase 3 CASSIOPEIA Study of Daratumumab in Multiple Myeloma at Pre-planned Interim Analysis [news release]. Copenhagen, Denmark. Published October 21, 2020. 

https://ir.genmab.com/news-releases/news-release-details/genmab-announces-ifm-hovon-and-janssen-achieve-positive-topline

2. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. 

. https://doi.org/10.1016/S0140-6736(19)31240-1.

Genmab recently announced positive topline results from part 2 of the Phase 3 CASSIOPEIA study examining daratumumab monotherapy as maintenance therapy to treat patients diagnosed with multiple myeloma.

Study Analyzing Daratumumab to Treat Patients with Multiple Myeloma Induces Positive Topline Results

 mutations in baseline circulating tumor DNA (ctDNA) is associated with inferior progression-free survival (PFS) and overall survival (OS) in patients with advanced hormone receptor (HR)-positive breast cancer treated with exemestane (Aromasin) versus fulvestrant (Faslodex), according to a combined analysis of the phase 3 SoFEA and EFECT trials published in 

“This work supports the argument for the use of liquid biopsies as part of routine care for those with advanced cancer, as they can be used to improve outcomes by ensuring that we select the most appropriate treatments,” Nicholas Turner, PhD, professor of Molecular Oncology at the Institute of Cancer Research (ICR) and head of the Ralph Lauren Centre for Breast Cancer Research at The Royal Marsden, said in a press release.

The phase 3 EFECT and SoFEA trials randomized patients with HR-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy to receive either 250 mg of fulvestrant or exemestane. Baseline serum samples from 227 patients in EFECT and baseline plasma from 161 patients in SoFEA were evaluated for 

The dual primary end points of the study were to assess the impact of 

 mutation status on PFS and OS in a combined analysis of both studies.

mutations were detected in 30% of baseline samples. Of those with the 

 mutation detected, PFS was 2.4 months (95% CI, 2.0-2.6) on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant (HR, 0.59; 95% CI, 0.39-0.89; 

 mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; 

Ultimately, there was an interaction observed between 

 mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant (

 = .04; restricted mean survival analysis). Further, patients without 

 mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant (

“It is clear from this study that there is an interaction between the 

 mutation, and the treatment chosen,” Turner explained. “The 2 trials examined here showed, without measuring 

 mutations, that exemestane and fulvestrant worked similarly. But by adding 

 status to the picture, we can see that is not the case. Patients with ESR1 mutations were at a higher risk of early progression and death if treated with exemestane.”

Importantly, the researcher emphasized that patients treated with fulvestrant in the EFECT and SoFEA trials were treated with a dose half that is used currently (250 mg of fulvestrant vs 500 mg of fulvestrant in the CONFIRM study) and this has important implications for interpreting the results of patients with undetected 

 mutations. Although there was no difference found between exemestane and fulvestrant in the 

-undetected group, this may reflect the lower dose of fulvestrant used; thus, it is reasonable to speculate that such patients treated with fulvestrant may have had improved PFS on a 500 mg dose of fulvestrant compared with exemestane.

Moving forward, the investigators suggested that further investigation of whether different 

 mutations have differing responsiveness to fulvestrant, or tamoxifen (Nolvadex), will still be necessary.

“Our data provides evidence of clinical utility of ctDNA liquid biopsies in breast cancer, suggesting the potential to improve outcome, to monitor for the presence of 

 mutations in advanced breast cancer, and to aid in selection of the most appropriate subsequent endocrine therapy backbone, if further aromatase inhibitor-based therapy is being considered,” the study authors concluded.

1. Turner NC, Swift C, Kilburn L, et al. ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials. 

2. New study sheds light on the best drug choices for some patients with advanced breast cancer [news release]. Published October 8, 2020. Accessed October 9, 2020. https://www.icr.ac.uk/news-archive/new-study-sheds-light-on-the-best-drug-choices-for-some-patients-with-advanced-breast-cancer

Detection of ESR1 mutations in baseline ctDNA was associated with inferior progression-free survival and overall survival in patients with advanced HR-positive breast cancer treated with exemestane versus fulvestrant.

Combined Study Analysis Determines Best Drug Choices for Patients with Advanced Breast Cancer

Findings from the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) support the feasibility and efficiency of using next-generation sequencing (NGS) to triage patients to investigational therapy, provided that a sufficiently large pool of agents is made available.

Importantly, this is the largest data set ever compiled on patients with tumors that have progressed on 1 or more standard treatments, or with rare cancers for which there is no standard treatment.

“Our exhaustive efforts to enlist all of the promising agents in NCI-MATCH established a new benchmark for the utility of next-generation sequencing in the conduct of clinical trials,” lead author Keith T. Flaherty, MD, a medical oncologist at Massachusetts General Hospital Cancer Center in Boston, said in a press release.

 “With time, the efficiency of using tumor genetic testing for broad-based clinical investigation will only increase.”

, tumor biopsy specimens from 5954 patients with refractory malignancies at 1117 accrual sites were centrally analyzed using NGS and selected immunohistochemistry in a master screening protocol. Notably, researchers only evaluated treatments which had demonstrated clear evidence of clinical benefit or at least promising preliminary efficacy in the proposed eligibility genotype in any tumor histology.

Overall, molecular profiling was found to be successful in 93.0% of specimens. Moreover, an actionable alteration was detected in 37.6%.

Following the application of clinical and molecular exclusion criteria, 17.8% of specimens were assigned, though 26.4% could have been assigned if all subprotocols had been available simultaneously. As of the study publication, 11 subprotocols had reached their accrual goal.

Notably though, actionability rates differed among histologies; for instance, the actionability rate for urothelial cancers was 35%, while for pancreatic and small-cell lung cancer the actionability rate was 6%. Additionally, multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively.

According to researchers, these rates may increase as more drugs become available, especially those that target common gene defects.

“The 6000-patient analysis from NCI-MATCH describes the genetic complexity that is characteristic of relapsed, refractory cancers,” Peter J. O’Dwyer, MD, a medical oncologist at the University of Pennsylvania and group co-chair of the ECOG-ACRIN Cancer Research Group, said in the release. “This publication represents an important milestone in the oncology field’s efforts to translate a genetic understanding of cancer into improved treatments.”

NCI-MATCH researchers also compared the tumor gene make-up of patients with 7 cancer types against The Cancer Genome Atlas (TCGA), including breast, bile duct, cervical, colorectal, lung, pancreatic, and prostate cancer. Ultimately, there were not many differences observed between the primary and metastatic databases. Known resistance mutations to targeted therapies were found to be numerically more frequent in NCI-MATCH than TCGA tumors, though not markedly so.

In order to better understand the differences in tumor gene make-up between primary and metastatic tumors, the investigators plan to compare the NCI-MATCH patients’ primary and metastatic tumors moving forward. Multiple treatment arms have also been opened in NCI-MATCH, with 38 arms of research currently ongoing.

“NCI-MATCH is a unique and ground-breaking trial that will continue to make major contributions in years to come as genomic findings from individual treatment arms, correlated with outcomes, are released,” Lyndsay Harris, MD, translational co-chair of NCI-MATCH and associate director of the Cancer Diagnosis Program and the Division of Cancer Treatment and Diagnosis at the NCI, said in the release.

1. Flaherty KT, Gray RJ, Chen AP, et al. Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). 

2. Genomic study of 6000 NCI-MATCH cancer patients leads to new clinical trial benchmarks [news release]. Philadelphia. Published October 13, 2020. Accessed October 14, 2020. https://ecog-acrin.org/news-and-info/press-releases/genomic-study-of-6000-nci-match-cancer-patients-leads-to-new-clinical-trial-benchmarks

Results from NCI-MATCH support the feasibility and efficiency of using next-generation sequencing (NGS) to triage patients to investigational therapy, provided that a sufficiently large pool of agents is made available.