Denise Myshko

fusion–positive solid tumors and baseline CNS metastases demonstrated durable intracranial activity with e

according to results of a small subpopulation analysis presented at the 2020 ESMO Virtual Congress.

 fusion-positive, TRK inhibitor-naïve solid tumors treated with entrectinib, the intracranial objective response rate (ORR) was 50% in all patients with baseline metastases and median intracranial duration of response (DOR) was 8.0 months. Median intracranial progression-free survival (PFS) was 8.9 months.

“The results of this updated analysis confirm entrectinib is associated with clinically meaningful and durable intracranial responses in patients with 

 fusion-positive tumors and baseline CNS metastases,” said Thomas John, MBBS, PhD, associate professor, senior clinical research fellow at the Olivia Newton-John Cancer Research Institute in Victoria, Australia.

 gene fusions are clinically actionable oncogenic drivers in solid tumors. CNS metastases are diagnosed in 10% to 30% of solid tumors and associated with poor outcome. Entrectinib is a potent inhibitor of 

 tyrosine kinases designed to cross the blood-brain barrier and achieve therapeutic levels in CNS.

Entrectinib is an oral medication that was approved, to treat adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are 

-positive, as well as adult and pediatric patients 12 years of age and older with solid tumors that have a 

In this analysis, intracranial tumor assessments were performed at the end of week 4 and every 8 weeks thereafter and were evaluated by blinded independent central review (BICR) using RECIST v1.1. Study endpoints were intracranial ORR, intracranial DOR, and intracranial PFS.

John previously presented data on 54 patients, which showed an intracranial ORR of 55% and non-estimable intracranial DOR. This updated analysis was conducted to confirm these findings in a larger cohort of patients.

In this analysis, data were analyzed for 74 patients with metastatic 

 fusion-positive, TRK-inhibitor-naïve solid tumors from 3 phase 1 and phase 2 trials: 1 patient from ALKA-372-001 (EudraCT 2012-000148-88), 2 patients from the dose-escalation STARTRK-1 (NCT02097810), and 71 patients from the STARTRK-2 (NCT02568267).

The data cut off for this analysis was October 31, 2018. This is a very heavily pre-treated population, and the majority had ECOG performance status. Of the 74 patients, 19 patients had investigator-assessed CNs metastases at baseline, and 16 were confirmed to have CNS metastases at baseline per BICR of 5 different tumor types, including NSCLC (8), thyroid (4), sarcoma (1), salivary (1), and breast (1). Of these 16 patients, 8 had measurable CNS metastases and were evaluable for response.

Entrectinib lead to high intracranial ORRs: 50.0% (95% CI, 24.7-75.4) in the analysis set of 16 patients and 62.5% (95% CI, 24.5-91.5) in the 8 patients with measurable CNS disease. The median intracranial DOR in the set of 16 patients was 8.0 months (95% CI, 6.7-NE) and was not estimable in measurable patients with CNS metastases.

Among patients who had baseline measurable disease, nearly all patients responded, John said during his presentation. The complete response was high, with 4 patients have a complete response, and 4 patients achieving a partial response. “Entrectinib has high intracranial activity across different tumor types,” he said.

Only 1 patient had disease progression. The patient with thyroid cancer had a reduction in the target lesion but had progression in non-target lesions, John said.

The PFS in the set of 16 patients was 8.9 months (95% CI, 5.9-14.3) and 10.1 months (95% CI, 2.8-NE) in the set of 8 patients who had measurable baseline disease.

There was a low rate of CNS disease progression. Only 3 out of 74 patients evaluated showed evidence of detected, scan-confirmed CNS progression. “This suggests that entrectinib may provide protection against the development of CNS metastases including some of these patients who had non-small cell lung cancer and breast cancer where there is a high rate of CNS progression,” John said.

Entrectinib was generally well tolerated in patients both with and without baseline CNS metastases, said John. In patients who had any type of neurologic adverse effects (AEs), the most common effects were dysgeusia, dizziness, and paresthesia. The safety population that was evaluated included all patients from these 3 studies and included 504 patients with 

 who received at least 1 dose of entrectinib.

John T. Intracranial efficacy of entrectinib in patients with NTRK fusion-positive solid tumours and baseline CNS metastases. Oral presentation European Society of Medical Oncology (EMSO) Virtual Congress 2020. September 17-21. Abstract #3640 

Rozlytrek. Prescribing information. Genentech. Revised August 2019. Accessed September 20, 2020. 

Articles

Patients with NTRK fusion–positive solid tumors and baseline CNS metastases demonstrated durable intracranial activity with entrectinib, according to results of a small subpopulation analysis presented at the 2020 ESMO Virtual Congress.





Intracranial Responses Are Induced With Entrectinib in NTRK+ Tumors

Futibatinib (TAS-120) demonstrated efficacy and tolerability when administered to patients with intrahepatic cholangiocarcinoma (iCCA) who harbor 

 fusions/rearrangements, according to results of an interim analysis of the FOENIX-CCA2 trial (NCT02052778) presented in a poster during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

Investigators recorded an objective response rate (ORR) of 37.3% (95% CI, 25.8-50.0) in this analysis of 67 patients with at least 6 months of follow-up. One patient (1.5%) had a complete response and 24 (35.8%) had partial responses.

Futibatinib is an oral, small molecule inhibitor of 

 fusions occur in 10% to 20% of patients with iCCA, with an expected 5-year survival rate of 24%. Currently, there is no standard treatment for advanced disease after first-line chemotherapy.

Responses were durable, lasting a median of 8.3 months, and 37% of patients remained on treatment at the median follow-up of 11.4 months. Investigators observed objective responses across patient subgroups, regardless of the number of prior treatment regimens and in patients with co-occurring genetic alterations in 

The disease control rate was 82.1% ­(95% CI, 70.8%-90.4%). Median time to response was 2.5 months (range, 1.4-2.7). The median duration of response (DOR) was 8.3 months (95% CI, 6.2 to not evaluable).

The median progression-free survival (PFS) was 7.2 months (95% CI, 4.0-15.2). At 6-months, the PFS rate was 61% (95% CI, 47.5%-72.0%) and the overall survival (OS) rate was 86% (95% CI, 74.7%-92.4%).

The targeted agent is being explored in an ongoing, global, open-label phase 2 study of patients with unresectable locally advanced or metastatic iCCA harboring an 

 fusion or rearrangement. A total of 103 patients were enrolled across 36 international sites from April 2018 to November 2019. Median follow-up in this planned analysis (database lock March 30, 2020) was 11.4 months. Investigators identified 

The primary end point was ORR as assessed by independent central radiological review per RECIST 1.1, confirmed by a second tumor assessment 4 to 6 weeks after the initial response. DOR, disease control rate (DCR), PFS, and safety were secondary end points.

Investigators noted the safety profile observed was consistent with this drug class. All patients experienced treatment-related adverse effects (TRAE) and 38 (57%) experienced a grade 3 TRAE.

Seven patients (10%) reported serious TRAEs. Migraine was the only serious TRAE reported in more than 1 patient (n = 2). Overall, 44 patients (66%) had a dosing modification because of a TRAE. There were 37 patients (55%) who required dosing interruption and 34 (51%) with dose reductions.

Eighteen patients (27%) experienced grade 3 or higher hyperphosphatemia. All cases resolved with medication and no patients discontinued treatment because of hyperphosphatemia.

Thirty-six patients (54%) discontinued because of clinical or radiological disease progression; no patients died while on treatment. Four patients discontinued treatment because AEs.

This trial also included a phase 1 dose-escalation phase, which established 20 mg once daily futibatinib as the maximum tolerated dose.

 Antitumor activity of futibatinib was also demonstrated across patients with various advanced tumor types (including cholangiocarcinoma) with a range of 

The phase 3 FOENIX-CCA3 (NCT04093362) trial of futibatinib versus gemcitabine/cisplatin in the first-line setting is underway. This is an open-label, multinational, 2-arm parallel, randomized study of patients with advanced, metastatic, or recurrent unresectable iCCA harboring 

 gene rearrangements. The trial is estimated for enrollment of 216 patients. The primary end point is PFS, with secondary outcome measures of ORR, DCR, OS, safety, and tolerability.

Futibatinib is also being studied in a phase 2 trial (NCT04024436) in patients locally advanced/metastatic breast cancer harboring 

 gene amplifications. This is an open-label, nonrandomized trial that will recruit 168 patients and assess ORR, clinical benefit rate, and 6-month PFS.

1. Bridgewater JA, Meric-Bernstam F, Hollebecque A, Valle JW, et al. Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/other rearrangements: Subgroup analyses of a phase II study (FOENIX-CCA2). Poster. European Society of Medical Oncology (EMSO) Virtual Congress 2020; September 17-21, 2020. Abstract #4493.

2. Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, et al. FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. 

. 2020;38(15):108. doi: 0.1200/JCO.2020.38.15_suppl.108

3. Bahleda R, Meric-Bernstam F, Goyal L, Tran B, et al. Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors. 

. 2020;S0923-7534(20)39928-2. doi:10.1016/j.annonc.2020.06.018.

Futibatinib demonstrated efficacy and tolerability when administered as treatment of patients with intrahepatic cholangiocarcinoma who harbor FGFR2 
fusions/rearrangements, according to interim analysis results presented in a poster during the the European Society of Medical Oncology Virtual Congress 2020


Futibatinib Induces Durable Responses in FGFR2+ Intrahepatic Cholangiocarcinoma

Adding a subcutaneous formulation of daratumumab (Darzalex Faspro) to the triplet regimen cyclophosphamide, bortezomib (Velcade), and dexamethasone (CyBorD) may hold promise for patients with newly diagnosed light chain (AL) amyloidosis who are in urgent need of new treatment options. Data from the phase 3 ANDROMEDA (NCT03201965) trial, which demonstrated the superiority of CyBorD plus subcutaneous daratumumab (Dara-CyBorD) versus CyBorD alone, were presented virtually during the 25th Congress of the European Hematology Association. The experimental combination resulted in deeper and more rapid hematologic responses and led to better clinical outcomes with an acceptable safety profile.

The combination of Dara-CyBorD therapy improved major organ deterioration progression-free survival (MOD-PFS) and resulted in substantially higher organ responses in patients with newly diagnosed AL amyloidosis, according to Efstathios Kastritis, MD, associate professor of clinical therapeutics/medical oncology at the National and Kapodistrian University of Athens in Greece.

Systemic AL amyloidosis is a rare disease characterized by insoluble amyloid fibril deposition in tissues and organs. There is no approved treatment, and about 30% of patients die within the first year of diagnosis. Treatment with the CyBorD combination has improved outcomes, but sustained hematologic response is needed to reverse amyloid-mediated organ dysfunction and improve overall survival.

The primary end point of the phase 3, randomized, open-label, active-controlled study was overall hematologic complete response (CR) rate in the intention-to-treat population. Secondary end points included MOD-PFS, organ response rate, time to hematologic response, survival, and safety.

Results showed that hematologic CR rate was 53% for Dara-CyBorD compared with 18% for CyBorD alone (OR, 5.1; 95% CI, 3.2-8.2; 

 <.0001). The 6-month organ response rate was nearly doubled for patients treated with the addition of subcutaneous daratumumab versus CyBorD alone for both cardiac (42% vs 22%) and kidney (54% vs 27%) responses.

The Dara-CyBorD combination achieved higher rates of overall hematologic response (92% vs 77%) and very good partial response or better (VGPR; 79% vs 49%) (FIGURE).

 Among responders, median time to VGPR or better was 17/60 days for the daratumumab arm compared with 25/85 days for CyBorD alone. MOD-PFS favored DARA-CyBorD-treated patients (HR, 0.58; 95% CI, 0.37-0.93; 

There were 388 patients randomized to either Dara-CyBorD (n = 195) or CyBorD (n = 193). All patients received weekly cyclophosphamide (300 mg/m

 orally or intravenously), bortezomib (1.3 mg/m

 subcutaneously), and dexamethasone (20-40 mg orally or intravenously) for six 28-day cycles. Subcutaneous daratumumab was administered weekly by injection in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter for up to 24 cycles.

The efficacy and safety profile of intravenous and subcutaneous daratumumab are well characterized. The agent showed no new safety concerns, according to Kastritis. The rate of discontinuation due to treatment-emergent adverse events (TEAEs) was 4% in both arms.

The most common grade 3/4 TEAEs occurring in more than 5% of patients treated on the daratumumab arm were lymphopenia (13% with Dara-CyBorD vs 10% with CyBorD), pneumonia (8% vs 4%, respectively), diarrhea (6% vs 4%), cardiac failure (congestive; 6% vs 5%), neutropenia (5% vs 3%), syncope (5% vs 6%), and peripheral edema (3% vs 6%). Fourteen patients (7%) experienced systemic administration-related reactions with daratumumab-CyBorD; all were grade 1/2 in severity, and most occurred during the fi rst infusion. A total of 56 deaths occurred in the entire trial, 29 patients treated with Dara-CyBorD and 27 who got CyBorD.

Daratumumab is the first and only subcutaneous CD38-directed antibody approved globally. In May of this year, the FDA approved the subcutaneous formulation alone and in combination for the treatment of adult patients with multiple myeloma.

The manufacturer responsible for producing daratumumab, Janssen Biotechnologies, collaborated with Halozyme Therapeutics to develop the subcutaneous form of the agent. Halozyme’s Enhanze system works to degrade hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue, thus allowing large volumes of the drug to be delivered in a single subcutaneous injection.

1. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. Presented at: 25th Congress of the European Hematology Association; June 11-21, 2020. Abstract LB2604. https://bit.ly/32eSmJU

2. FDA approves daratumumab and hyaluronidase-fi hj for multiple myeloma. FDA. May 1, 2020. Accessed July 13, 2020. https://bit.ly/2BYcnKd3

3. Enhanze drug delivery technology. Halozyme. Accessed June 3, 2020. https://bit.ly/3fqTjm2

Adding a subcutaneous formulation of daratumumab to the triplet regimen cyclophosphamide, bortezomib, and dexamethasone may hold promise for patients with newly diagnosed light chain amyloidosis who are in urgent need of new treatment options, according to a clinical trial.

Patients With AL Amyloidosis May Benefit From Subcutaneous Daratumumab/CyBorD Combination

In the face of canceled medical meetings this spring, continuing medical education (CME) offerings from Physicians’ Education Resource, LLC® (PER®) were quickly transitioned from an in-person format to virtual presentations that have the ability to reach more medical specialists nationwide (

take our POLL on the impact of a virtual meeting format at the end of this article

). Additionally, the organization made a concerted effort to add new programs to its roaster specifically on the treatment of patients during the coronavirus disease 2019 (COVID-19) pandemic.

Early on in the pandemic, PER® and its parent company MJH Life Sciences™, the largest privately held, independent, full-service medical media company in North America, moved quickly to bring oncologists the most up-to-date information on treating patients with cancer through these challenging times. PER®started hosting webinars focused on COVID-19 and has now launched a series, “

COVID-19 and Cancer Care: What Oncologists Need to Know Today

.” The first live CME-certified COVID-19 webinar that aired on March 23 drew a virtual audience of more than 1200 attendees, who tuned in to hear oncology experts discuss the risk and potential impact of COVID-19 for patients with hematologic and solid tumor malignancies, optimal preventive protocols for how oncologists could protect themselves and their staffand across inpatient and outpatient settings, and therapeutic strategies.

The “COVID-19 and Cancer Care” program has evolved into an ongoing live meeting series, occurring every Monday, and features insights from eminent practicing oncologists.

Beyond COVID-19–focused online CME activities and webinars, the transition of various live events and conferences from an in-person to a digital format has been a driving force at PER®. One innovation is the ASCO Direct Highlights™ series featuring expert analysis of clinical findings presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Annual Meeting. These sessions aired live in June on PER®’s website to registered participants.

PER® also quickly transformed its multiday in-person conferences to a virtual format. Just 1 day before the 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies conference was scheduled to take place on March 13, New York Gov. Andrew M. Cuomo formally banned all public gatherings of more than 500 people. MJH Life Sciences™, however, had already made the decision days before to pivot and present the conference as a virtual meeting.

According to meeting organizers, it’s difficult to mirror an in-person program. Clinicians come to events not only to stay up-to-date on the content, but also to interact with the experts and ask them questions.

“The biggest opportunity we had, which was also the biggest challenge, was how to create highly interactive programs where there can be Q&A, where attendees can interact with the faculty in real-time, and where faculty can poll the audience and comment on what their results are in real-time. These are the components that really foster that interaction with a capital ‘I,’” Phil Talamo, CHCP, president of PER®, said regarding the changes to the meeting format. “And it is something that attendees have come to expect from a first-class PER® educational session.”

Talamo and his team at PER® rose to meet the challenge, converting 100% of programing that was scheduled from in-person events to virtual events. Additionally, the company has seen a low opt-out rate, and many repeat attendees. Feedback from the events has been that the programing is engaging and interactive, and attendees like the ability to be able to ask questions.

Participation in the virtual meetings mirrors that of the in-person events. Attendees come for the content and the faculty, Talamo said. “The programs that do well live and in person also do well online. For virtual programming, we have been designing them to be content-relevant based on timeliness. Depending on the data cycle, the format may change. We’ve done a number of post-ASCO webcasts and depending on the ASCO data [that we are presenting], we’re going to have varying methods of disseminating data, with both traditional lectures that provide detailed analyses of new studies, and also panel discussions such as Medical Crossfire to address diverse perspectives of data interpretation.”

Despite the disruption caused by the COVID-19 pandemic, PER® has continued its mission to keep community oncology care providers informed and connected with experts in the field.

“We fulfilled our commitment to the community to make sure that education was available. We have proven that we can continue to be the trusted provider and resource in education through both virtual and on-demand activities. So even if this [pandemic] continues into next year, our incredible team has done a very nice job of keeping the community armed with the data they need and the expertise to care for their patients,” he said.

Although Talamo is unsure when live events will resume, he expects that when they do, there will likely be a virtual component to all events. Clinicians may still be unable to attend because of institution restrictions on travel. These clinicians, however, depend on the data that are provided through these events to treat their patients. There is so much uncertainty about COVID-19, and no one knows what is going to happen next, he said.

“The one thing we do know is people are still going to get cancer, and they are still going to need state-of-the-art treatment. Things are going to continue to change and evolve. We want to make sure we are doing all we can as a trusted provider of education to support clinicians. The impact of COVID is real, and the spirit of the oncology community is going to lead to a positive path forward,” Talamo said.

Fewer interactions with individuals in the pharmaceutical industry

More time to learn about practice-changing breakthroughs 

Fewer connections between potential collaborating investigators

In the face of canceled medical meetings this spring, continuing medical education offerings from Physicians’ Education Resource, LLC®  were quickly transitioned from an in-person format to virtual presentations that have the ability to reach more medical specialists nationwide.

Author | Denise Myshko

Articles

Intracranial Responses Are Induced With Entrectinib in NTRK+ Tumors

Futibatinib Induces Durable Responses in FGFR2+ Intrahepatic Cholangiocarcinoma

Patients With AL Amyloidosis May Benefit From Subcutaneous Daratumumab/CyBorD Combination

Live, Virtual Events Take Center Stage for PER