Compared with DNA sequencing alone, a multi-omics approach to personalized therapy that incorporates information about actionable oncogenic drivers with critical biological data was shown to be feasible in the metastatic breast cancer setting, according to a presentation at the American Association of Cancer Research Annual Meeting 2021.

“We demonstrate the feasibility of implementing a deep real-time analytics platform for [patients with metastatic breast cancer] that can provide new insight into therapeutic opportunities,” Ben L. Kong, PharmD, of Oregon Health & Science University, said during a presentation of the data. “The observed clinical responses support the use and investigation of this approach.”

The SMMART program, which stands for Serial Measurements of Molecular and Architectural Responses to Therapy, has multiple clinical and research objectives such as real-time adaptation of therapy to each patient’s needs, durable and tolerable tumor control over the life of the patient, and the ability to identify resistance mechanisms and biomarkers of cancer treatment.

When the patient enters the program, data are generated to design a therapy plan. Patients are then monitored over the course of treatment to identify tumor response. If progression occurs, they are invited back to obtain additional biopsies.

“Internally, the program is collecting a large amount of data. We start off with a tumor biopsy and blood followed by clinical data and also anatomic imaging,” Kong said. “All the information that we collect are then passed along to the data management system, which then is available for both the research tumor board and the clinical tumor board to review and access.”

From January 2017 to January 2020, 53 patients consented for screening and biopsy with 38 patients enrolled. After analytics were generated and disease progression occurred, patients were assigned to either a matched or an unmatched therapy.

The multi-omics clinical tumor board was presented DNA- and RNA-level data, such as whole-exome sequencing and whole-transcriptomic sequencing, and laboratory results such as immunohistochemistry and tumor markers. After that, optimal therapy management was recommended, consisting of either additive care, off-label treatment, or a clinical trial.

Enrolled patients had a median age of 56 years (range, 32-75), were majority White (89%), and had a median of 3 prior lines of therapy (range, 0-13); all patients were female. Most biopsies (n = 63) were collected from the lymph nodes (35%), liver (27%), soft tissue (11%), or bone (10%). Fifteen patients had serial biopsies taken, which consisted of 2 or more samples.

A cutoff of 1.3 for the ratio of second progression-free survival (PFS) to first PFS (PFS2:PFS1) was used in the 12 patients who received match therapy. Of those, 8 patients had a PFS2:PFS1 ratio that met or surpassed the predetermined threshold.

Kong specifically detailed the results in 3 patients treated with matched therapy. The first had tumor heterogeneity identified through serial biopsies but was initially found to be estrogen receptor (ER)–positive with tamoxifen administered at disease recurrence. Subsequent biopsies in the liver following mixed responses revealed some to have ER-negative and triple-negative histologic subtypes. Unfortunately, treating clinicians were not able to determine an effective therapy for this patient.

In another case, a novel combination of a checkpoint plus a PARP inhibitor was used in a patient with serial biopsy monitoring. Of note, apparent mechanisms of resistance in the MAP kinase pathway were revealed and the patient was switched to bridging therapy with chemotherapy for tumor disease management. Discussion by a tumor board led to the patient receiving a PARP inhibitor plus the MEK inhibitor cobimetinib (Cotellic).

Another patient with an exceptional tumor response initially presented to the program on doxorubicin therapy with rising tumor markers and a progressing liver lesion that was identified as ER negative and HER2 negative with an activating 

 activating mutation. Research analytics also came back indicating activation along the HER2 axis. As a result, the patient was started on trastuzumab (Herceptin) with a dramatic decrease in tumor markers.

“The best way to fulfill the essence of the tumor board is to make sure that the best treatment is recommended,” Kong said. “[We want to] make sure that we identify the best treatment that matches with the evidence.”

Kong BL, Johnson BE, Keck JM, et al. SMMART Program: a multi-omics tumor board with a focus on breast cancer. Presented at: American Association of Cancer Research Annual Meeting 2021. April 9-14, 2021. Abstract LB010.

Articles

During a presentation at the American Association of Cancer Research Annual Meeting 2021, Ben L. Kong, PharmD, described the SMMART program, which pairs genetic and clinical information to find the best therapies for patients with breast cancer who progress on standard therapies.

Multi-Omics Approach to Breast Cancer May Provide Better Information Versus Biomarker Assessment Alone

 sat down for a conversation with David Johnson, chairman and CEO of Enveric Biosciences. Johnson thoroughly discussed the background of the biosciences company and detailed the endocannabinoid products Enveric is developing to positively impact quality of life for patients with glioblastoma and other cancers.

Don’t forget to subscribe to the “Oncology Peer Review On-The-Go” podcast anywhere podcasts are available.

Podcasts

CancerNetwork®’s podcast features an interview with the chairman and CEO of Enveric Biosciences, David Johnson, to discuss the latest in their development of endocannabinoid products.

Oncology Peer Review On-The-Go: 1-on-1 with David Johnson: Enveric’s Endocannabinoid Products for Glioblastoma

Data from the phase 1/2 ADVL1312 trial (NCT02095132) presented virtually at the AACR Annual Meeting 2021 found that in a cohort of pediatric patients with neuroblastoma, therapy with adavosertib plus irinotecan achieved the study’s protocol-defined efficacy end point.

More, adavosertib plus irinotecan also showed the potential to benefit patients with 

-mutant tumors, with further validation required for this effect.

“In order to look for an early signal of activity and to obtain more information regarding toxicity of the recommended phase 2 dose, the ADVL1312 trial proceeded with a phase 2 expansion in 3 pediatric disease-specific cohorts,” presenting author Kristina A. Cole, MD, PhD, of Children’s Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, said in the presentation of the data.

The 3 pediatric cohorts analyzed in the expansion phase of this trial included neuroblastoma (n = 20), medulloblastoma with central nervous system (CNS) embryonal tumors (n = 10), and rhabdomyosarcoma (n = 10).

Overall, 3 objective responses were recorded from 16 eligible patients in the neuroblastoma cohort, which met the protocol-defined efficacy end point. Meanwhile, there was 1 recorded objective response in the group with medulloblastoma and CNS embryonal tumors and no responses with rhabdomyosarcoma, respectively.

The investigative team also sought to determine factors correlated with clinical response, focusing on the 

 chromatin remodeler gene. Twelve of the archival ADVL1312 tumors were evaluated.

Ultrabright telomeric foci (UBTF) were present in tumors from 2 of the 3 patients who experienced an objective response. More, ATRX deficiency was present in 4 of the 9 patients with clinical response or stable disease.

Common grade 3 or higher adverse events included neutropenia (5 events in the neuroblastoma cohort; 4 events in medulloblastoma; and 3 events in rhabdomyosarcoma), lymphopenia (4 events; 2 events; and 1 event, respectively), and leukopenia (2 events vs 2 events vs 0 events).

More, the toxicity profile of ADVL1312 featured no dose-limiting toxicities at cycle 1 or later at the maximum-tolerated dose. Regardless of this finding, and although the combination was well tolerated, the investigative team notes that oral irinotecan is not palatable.

The investigative team utilized the phase 2 data from irinotecan to inform the efficacy end point for the combination therapy analyzed in the expansion portion of ADVL1312. In order to define the therapy as effective in the neuroblastoma and rhabdomyosarcoma cohorts, 3 objective responses out of 20 eligible patients were required. More, 6 response out of 19 eligible patients were required for efficacy in the medulloblastoma with CNS embryonal tumors cohort.

“Several of the limitations of this study relate to the fact that it was a phase 2 expansion,” explained Cole. “For example, patients were eligible for response regardless of if they completed a cycle of therapy or had their disease reevaluated. One-third of patients discontinued therapy with stable disease or better.”

Median age for patients in the neuroblastoma cohort was 9 years (range, 6-19), with a majority of patients being male (65%) and White (60%). In the medulloblastoma cohort, the median age was 13.5 years (range, 6-20), with a majority of patients female (60%) and White (70%). Lastly, the rhabdomyosarcoma cohort reported a median age of 11 years (range, 4-16) with 80% of patients reporting as male and 90% of patients reporting as White.

Looking ahead, because of the satisfaction with the preliminary findings in this expansion trial, Cole noted that an adavosertib pediatric development plan is being discussed.

Cole KA, et al. Pediatric phase 2 trial of the WEE1 inhibitor adavosertib (AZD1775) and irinotecan; A Children’s Oncology Group Study (ADVL1312). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT029.

Data presented at the virtual AACR Annual Meeting 2021 showed that a phase 2 trial examining combination treatment with adavosertib plus irinotecan met its protocol-defined efficacy end point in a cohort of pediatric patients with neuroblastoma.

Adavosertib Plus Irinotecan Combination Met Efficacy End Point for Pediatric Neuroblastoma

 highlights the most important content from the previous week in oncology news.

Among the top news from last week are actions by the FDA that brought medical devices and systemic therapies closer to use in the real-world setting. First, cryoablation technology earned breakthrough therapy designation to treat patients with early breast cancer. Then, sacituzumab govitecan (Trodelvy) was granted full approval for the treatment of patients with triple-negative breast cancer.

Cryoablation Technology for Early Breast Cancer Earns Breakthrough Therapy Designation

The next-generation cryoablation technology ProSense was granted breakthrough device designation to treat certain patients with T1 breast tumors.

The technology uses liquid nitrogen–based cryoablation for a minimally invasive destruction of tumor cells. This designation from the FDA will allow for an accelerated review and feedback from the agency through the development process to commercialization.

MRI Before Biopsy Led to Improved Benefit-Harm Profile, Cost-Effectiveness for Prostate Cancer

Investigators used a hypothetical cohort of men with prostate cancer to test the benefits associated with MRI imaging before biopsy in regard to age-based and risk-stratified screening.

The observed improvements associated with an MRI-first pathway were greater when utilizing a risk-stratified screening method based on age and polygenic risk profile, which warrants further prospective evaluation.

FDA Grants Full Approval to Sacituzumab Govitecan for Triple-Negative Breast Cancer

Following last year’s accelerated approval designation, the FDA granted regular approval to sacituzumab govitecan to treat patients with triple-negative breast cancer.

The approval comes following positive safety and efficacy data for 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer who relapsed after 2 or more prior systemic therapies, with at least 1 therapy for metastatic disease, reported from the multicenter, open-label, randomized ASCENT trial.

Recombinant Adenovirus 5 Vaccine Shows Promise Against Castration-Resistant Prostate Cancer

A second-generation human adenovirus 5 immunotherapy vaccine has activity in patients with metastatic castration-resistant prostate cancer who are not responding to other available therapies.

The second-generation human Ad5 immunotherapy vaccine targeting tumor-associated antigens (TAA) of prostate-specific antigen, MUC-1, and brachyury showed immune activation in 17 patients evaluated, with all participants mounting a T-cell response in at least 1 TAA.

Long-Term OS Data for Olaparib Maintenance in Ovarian Cancer Show Clinically Meaningful Boost

With more than 5 years of follow-up, results from the SOLO2 trial of olaparib (Lynparza) maintenance in relapsed, high-grade serous or endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, were reported and showed superiority of the agent over placebo.

 indicate a 26% reduction in the risk of death with active versus placebo therapy (HR, 0.74; 95% CI, 95% CI, 0.54-1.00; 

 = .054) and represent a clinically meaningful improvement in this patient group.

 to stay up to date on the latest in oncology.

Take a look back at some of the important news and notes from last week in the world of oncology, featuring news from the FDA and articles about prostate cancer, ovarian cancer, and more.

CancerNetwork®’s Week in Review: April 12, 2021

Since the arrival of mRNA COVID-19 vaccines, new questions have emerged about how science can rally to harness future medical breakthroughs for cancer. mRNA vaccine technology shares similarities with targeted anticancer therapies. Therefore, key lessons from this pandemic could apply to the development of an infrastructure that could mean earlier cancer interventions.

Dr. Maurie Markman, President of Medicine & Science at Cancer Treatment Centers of America, sat down with 

 to discuss mRNA vaccines, what we can learn from the development of these products for COVID-19 prevention, and how these lessons can apply to cancer therapies.

This segment comes from the CancerNetwork® portion of the MJH Life Sciences™ Medical World News®, airing daily on all MJH Life Sciences™ channels.

Videos

During a Deep Dive segment of Medical World News®, CancerNetwork® sat down with Maurie Markman, MD, to discuss how lessons learned from the development of mRNA vaccines for COVID-19 can translate to cancer research.

Medical World News®: CancerNetwork Discusses mRNA Vaccines With Maurie Markman, MD

The FDA has accepted and granted priority review to a biologics license application (BLA) for tisotumab vedotin as therapy for patients with recurrent or metastatic cervical cancer whose disease progressed during or following chemotherapy treatment, according to Seagen Inc. and Genmab A/S who are responsible for developing the agent.

The agency has set a target action date of October 10, 2021 for an approval decision under the Prescription Drug User Fee Act. The BLA was originally submitted in February of this year.

“The FDA’s filing of the tisotumab vedotin BLA with priority review marks an important step forward for this ADC [antibody-drug conjugate] as a potential treatment for patients with recurrent or metastatic cervical cancer,” Roger Dansey, MD, chief medical officer at Seagen, said in a press release. “We are collaborating closely with the FDA throughout the review process to make this important therapy available to patients.”

Tisotumab vedotin is an investigational ADC directed at tissue factor, which is known to be highly prevalent in cervical cancer and is linked with cancer pathophysiology and poor prognosis, and is covalently linked to the microtubule-disrupting agent MMAE via a protease-cleavable linker. Additionally, it is co-opted by tumor cells to promote tumor growth, angiogenesis, and metastasis.

The BLA submission was based on results of the phase 2 single-arm innovaTV 204 trial (NCT03438396) which is examining tisotumab vedotin monotherapy in patients with previously treated, recurrent, or metastatic cervical cancer. 

Results of the trial were previously presented

 at the European Society for Medical Oncology 2020 Virtual Congress.

Results showed that tisotumab vedotin had the ability to induce an objective response rate (ORR) of 24% (95% CI, 15.9%-33.3%) in patients with recurrent and/or metastatic cervical cancer who were previously treated with doublet chemotherapy and bevacizumab (Avastin), which was comprised of complete responses in 7% of patients and partial responses in 17%. The median response duration was 8.3 months (95% CI, 4.2-not reached), with a median time to response of 1.4 months (range, 1.1-5.1).

The median progression-free survival in the patient cohort was 4.2 months and median overall survival was 12.1 months. Rates at 6 months were 30% and 79%, respectively. Of note, clinically meaningful responses were observed regardless of tumor histology, lines of prior therapy, responses to prior systemic treatment, and receipt of frontline doublet chemotherapy with bevacizumab.

Tisotumab vedotin had a manageable toxicity profile with no new safety signals identified. The most common treatment-related adverse events (TRAEs) with an incidence rate of 10% or higher included alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), dry eye (23%), myalgia (15%), anemia (12%), asthenia (12%), arthralgia (12%), decreased appetite (11%), keratitis (11%), and pruritis (10%). Most of these events were grade 1/2 in severity with grade 3/4 TRAEs occurring in 28% of patients. Of the 4 patients who died, 1 was due to septic shock that was considered to be treatment related.

“We are pleased that the tisotumab vedotin BLA has been accepted with priority review by the FDA as there is an unmet need for effective therapies for women with recurrent or metastatic cervical cancer, who have disease progression on or after chemotherapy,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in a press release. “This is an important milestone for Genmab as it brings us closer to our goal of bringing differentiated therapies to patients and transforming cancer treatment.”

1. Seagen and Genmab Announce U.S. FDA Filing Acceptance for Priority Review of Tisotumab Vedotin Biologics License Application for Patients with Recurrent or Metastatic Cervical Cancer. News release. Seagen Inc. and Genmab A/S. April 9, 2021. Accessed April 12, 2021. https://bit.ly/3mDRNRY

2. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. 

. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

Based on results of the phase 2 innovaTV 204 trial, the FDA granted priority review to tisotumab vedotin as a potential therapy for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

FDA Grants Priority Review to Tisotumab Vedotin for Recurrent/Metastatic Cervical Cancer

The selective MCL-1 inhibitor AMG 176 plus gilteritinib (Xospata) as a combination treatment synergistically targeted preclinical models of 

 internal tandem duplication (ITD)–mutated acute myeloid leukemia (AML), according to early data presented at the virtual AACR Annual Meeting 2021.

Specifically, data showed that there was a strong synergistic effect, with a combination index of <0.3, reported in 2 

-ITD mutated AML cell lines that received the combination. Additionally, AMG 176 plus gilteritinib led to an increase in MCL-1 and BCL-2–like protein 11 (BIM) expression in vitro, a decrease in BIM/MCL-1 interaction, and a significant increase with apoptosis.

In mice that were treated with the combination (n = 10), tumor regression was reported in 92.8% at 22 days after tumor implantation, which included 50% of mice being tumor free. The tumor growth inhibition rate at 22 days following tumor implantation was 73.9% in mice that received gilteritinib alone and 76.1% with AMG 176 alone.

“Our results show that AMG 176 plus gilteritinib treatment was effective and well tolerated in mouse models of AML, which supports further evaluation in a clinical setting,” Chen Xiaoyue, a post-doctoral research fellow in Oncology Research, Amgen, the developer of AMG 176, and coinvestigators wrote in a poster that was presented during the meeting.

The 5-year survival rate for patients with AML is 25%, and 

 is the most frequently mutated gene in the malignancy. About 25% and 8% of patients with this abnormality harbor 

-ITD mutations and FLT3-tyrosine kinase domain mutations, respectively.

Gilteritinib is a potent, selective oral FLT3 inhibitor that is currently approved by the FDA for the treatment of adult patients with 

 mutation—positive relapsed/refractory AML. The approval was based on data from the phase 3 ADMIRAL study (NCT02421939), in which the rate of complete remission (CR) or CR with partial hematologic recovery was 21% (n = 29; 95% CI, 14.5-28.8) with gilteritinib at a median follow-up of 4.6 months.

However, combination therapy to overcome resistance to gilteritinib in patients with 

Furthermore, the study authors expressed that 

 mutations are antiapoptotic, and MCL-1, which is an antiapoptotic protein and is said to have a critical role in AML cell survival and drug resistance, is commonly expressed in AML. AMG 176 is defined as a highly potent and selective MCL-1 inhibitor that induces rapid commitment to apoptosis in AML.

In the preclinical study, investigators measured the combination index of AMG 176 plus gilteritinib, conducted an immunoblot experiment, conducted a reverse transcription (RT)-polymerase chain reaction (PCR) assay, an MCL-1:BIM complex immunoassay, evaluated co-immunoprecipitation, generated BIM knockout cell lines, and evaluated the in vivo efficacy for the combination and an in vivo BAK activity test.

For the combination index, MOLM 13 and MV4-11 cells were seeded in 96 well plates at 1000 cell/well in 100 μl media, and cells received AMG 176 at EC70 concentration and gilteritinib at EC50, EC70, and EC90 concentrations. The viability of cells was analyzed 72 hours following therapy through the CellTiter-Glo luminescent cell viability assay, and the combination index was calculated via Calcasyn software. Here, investigators noted that AMG 176 synergizes with gilteritinib in 

-ITD–mutant AML cell lines, and BIM knockout was found to significantly reduce the synergistic effect between AMG 176 and gilteritinib.

In the immunoblot experiment, MOLM 13 and MV4-11 cells received gilteritinib at 20 nM for 2, 4, 8, 16, or 24 hours. The cells were washed with phosphate-buffered saline, lysed in a radioimmunoprecipitation buffer on ice, and lysates were pre-cleared via centrifugation at 4 degrees Celsius followed by DCTM protein assay analysis to determine the protein concentration.

In the RT-PCR assay, MOLM 13 and MV4-11 cells received dimethyl sulfoxide (DMSO), 250 nM of AMG 176, 20 nM of gilteritinib, or 20 nM of gilteritinib and 250 nM of AMG 176 for 2 days. The total RNA were extracted via RNeasy Kits, and MCL-1, BCL-2, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA levels were tested via SYBR Green qPCR.

The MCL-1 and BCL-2 mRNA levels were normalized through GAPDH mRNA levels before being normalized against DMSO treatment control. Data showed that MCL-1 protein expression is increased in samples that received gilteritinib alone or in combination with AMG 176. Additionally, the portion of MCL-1 sequestering BIM significantly decreased in the combination-treated samples vs DMSO control (

Additionally, in the preclinical models, gilteritinib was found to increase BIM expression, and overexpressed BIM proteins were sequestered by MCL-1 and BCL-2 following treatment with the FLT3 inhibitor. BIM was released from the BIM/MCL-1 complex after treatment with both drugs; however, compared with gilteritinib monotherapy, the amount of BIM that was sequestered by BCL-2 did not increase with AMG 176 plus gilteritinib.

When generating the BIM knockout cell lines by CRISPR/Cas9 technology, in which MV4-11 cells were sent to Synthego for engineering and 3-guide RNAs that were located at the second exon of the 

 gene can produce multiple BIM isoforms through alternative splicing.

For in vivo efficacy of the combination, 5 x 106 MV4-11 cells were injected into female athymic nude mice. The mice were randomized into 4 groups 12 days following tumor implantation, with 10 mice in each group. AMG 176 was given at 30 mg/kg on a schedule of 2 days on/5 days off for 2 weeks; gilteritinib was given at 3 mg/kg daily. Mouse body weight and flank tumor size were measured twice weekly.

For the in vivo BAK activity, the student’s t-test values were as follows: vehicle vs AMG 176 (

 = .2504), and gilteritinib vs combination (

 = .0157). No significant decrease in body weight was observed between the 2 groups.

1. Chen X, Caenepeel S, Belmontes B, et al. Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract 1050.

2. FDA Prescribing Information: Xospata (gilteritinib) tablets, for oral use. Accessed April 11, 2021. 

The selective MCL-1 inhibitor AMG 176 plus gilteritinib as a combination treatment synergistically targeted preclinical models of FLT3 internal tandem duplication–mutated acute myeloid leukemia.

AMG 716 Plus Gilteritinib Demonstrates Effective Preclinical Activity in FLT3-ITD+ AML

® sat down with Ronnie Shapira-Frommer, MD, to discuss research that was presented at the 

Society of Gynecological Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer

Shapira-Frommer discussed multidisciplinary care in the treatment of various gynecologic malignancies and how the data at the meeting facilitate this approach.

We have to face patients’ cancer as a multidisciplinary team with the strength of each expertise, including surgical, radiotherapy, and medical oncologist joined together. This is unique for this field of treatment. Pushing forward with the preclinical studies and with the data [from the SGO Annual Meeting], we can move forward patient care in the best of their interest, and for us as well.

CancerNetwork® spoke with Ronnie Shapira-Frommer, MD, during the Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women’s Cancer about her thoughts on the effect of the conference content across multidisciplinary specialties.

Ronnie Shapira-Frommer, MD, Discusses Multidisciplinary Care to Treat Gynecologic Malignancies 

According to data presented during the 2021 Virtual American Association for Cancer Research Annual Meeting, patients with non‒small cell lung cancer (NSCLC) with undetectable circulating tumor (ctDNA) 

ex14) following treatment with savolitinib are more likely to have positive progression-free and overall survival outcomes.

ex14 clearance upon savolitinib treatment was correlated with significantly longer progression-free survival [PFS] and overall survival [OS] compared with those who had detectable 

ex14,” said lead author Yongfeng Yu, MD, of the Shanghai Chest Hospital, Shanghai Jiao Tong University in Shanghai, China.

He cautioned the sample size was small and confirmation of the finding with a larger sample size was needed.

The median PFS for patients treated with savolitinib who had undetectable 

ex14 (n = 14) was 30.3 months (95% CI, 6.8-NC) with a hazard ratio (HR) of 0.72 (95% CI, 0.28-1.87; 

 = .501). The median OS for these patients was 35.8 months (95% CI, 14-NC) with an HR of 0.89 (95% CI, 0.25-3.18; 

ex14 following treatment (n = 10), the median PFS was 5.5 months (95% CI, 0.66-5.6) with an HR of 4.94 (95 CI, 1.83-13.36; 

 = .002). The median OS for these patients was 8.7 months (95% CI, 0.8-10.6). HR was 7.06 (95% CI, 2.39-20.89; 

For patients treated with savolitinib who were non-evaluable for 

ex14 (n = 22), the median PFS was 4.1 months (95% CI, 4.0-6.9). HR was 3.45 (95% CI, 1.48-8.03; 

 = .006). The median OS for these patients was 10.6 months (95% CI, 4.8-12.0). HR was 5.88 (95% CI, 2.24-15.47; 

ex14 was undectable for 20 patients at baseline. The median PFS for those patients was 13.8 months (95% CI, 4.2-22.1) and the median OS was not calculable.

Investigators also studied concurrent gene alterations with METex14 and noted alterations with likely resistance to savolitinib including 

 tyrosine kinase inhibitor. The agent previously demonstrated clinical efficacy and a manageable safety profile in Chinese NSCLC patients with METex14 alterations in a phase 2 study (NCT02897479).

In the analysis presented at AACR, investigators studied ctDNA analysis of 

ex14 at baseline and clearance upon treatment using next generation sequencing, QIAamp Circulating Nucleic Acid Kit from Qiagen. They collected plasma samples pre-dose and at tumor assessment visits, until disease progression or end of treatment. Data cut-off was August 2020.

Sixty-six patients provided baseline plasma samples, of which 

ex14 ctDNA was detectable in 46 (70%) patients. Of these patients, investigators were able to evaluate 24 patients for clearance of 

ex14. Fourteen of those 24 achieved ctDNA clearance with a median time to clearance of 1.4 months of treatment.

In a previously published analysis of patients in this phase 2 study, savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in 

 As of October 31, 2019, 593 patients were pre-screened/screened and 87 were identified as having 

ex14+; 70 of these patients were treated.

Sixty-one patients in this study were efficacy evaluable by independent review committee assessment. The objective response rate was 47.5% (95% CI, 34.6%-60.7%) with a disease control rate of 93.4% (95% CI, 84.1%-98.2%). The median duration of response has not been reached. The median PFS was 6.8 months (95% CI, 4.2-13.8) among all treated patients.

The most common (greater than or equal to 20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of grade 3 or higher TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% patients, the most common of which are liver injury and hypersensitivity (2.9% each).

The therapy’s developer, Hutchinson China MediTech, has applied for regulatory approval in China for the treatment of NSCLC with 

Ex14 skipping mutations, the first application globally and the first for a selective 

 inhibitor in China. China’s National Medical Products Administration has granted the therapy priority review status.

1. Yu Y, Ren Y, Fan J, et al. ctDNA analysis in the savolitinib phase II study in non‒small cell lung cancer (NSCLC) patients (pts) harboring 

ex14). Presented at: 2021 AACR Virtual Annual Meeting; April 10-15, 2021; Virtual. Poster CT158

2. Lu S, Fang J, Li X, et al. Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring 

 2020; 38, no. 15_suppl:9519-9519. doi: 10.1200/JCO.2020.38.15_suppl.9519

3. Chi-Med’s NDA for savolitinib in non‒small cell lung cancer granted priority review in China. Hutchinson China MediTech Limited. News release. July 28, 2020. Accessed April 10, 2020. https://www.hutch-med.com/nda-for-savolitinib-in-nsclc-granted-priority-review-in-china/

Patients with non‒small cell lung cancer with undetectable circulating tumor MET Exon 14 following treatment with savolitinib are more likely to have positive progression-free and overall survival outcomes.

Improved PFS and OS Correlated With Undetectable METex14 Following Savolitinib in NSCLC

Adding parsaclisib to the ruxolitinib (Jakafi) treatment of patients with myelofibrosis (MF) who had a suboptimal response on a standard dose of ruxolitinib alone led to improvements in spleen volume reduction (SVR) and symptom burden, according to data from a phase 2 study (NCT02718300) presented during the virtual AACR Annual Meeting 2021.

Responses to ruxolitinib with a parsaclisib add-on in the study occurred early on in the course of treatment and were durable. Moreover, the combination appeared well-tolerated in patients with MPNs.

The JAK 1/2 inhibitor ruxolitinib has long demonstrated the ability to improve outcomes like spleen volume, symptom burden, and survival in patients with MF. There is a subset of patients, however, who either have suboptimal responses to ruxolitinib or whose responses decline over time. Preclinical research into these phenomena suggested that activation of the PI3K pathway could benefit this patient population, therefore warranting the use of the next-generation PI3K inhibitor, parsaclisib.

To test the JAK and PI3K inhibitor combination in patients with MF, patients aged 18 years or older with primary or secondary MF were enrolled in the study. Patients were required to have an ECOG performance status of 2 or lower and have had a suboptimal response to ruxolitinib monotherapy after being treated with the agent at 5 to 25 mg twice daily for at least 6 weeks. On prior treatment with ruxolitinib, it was required that patients achieved stable disease that lasted at least 8 weeks and have a spleen that is over 10 cm below the left subcostal margin at the time of screening. Alternatively, patients could be eligible for the study with a spleen 5 cm to 10 cm below the left subcostal margin along with active MF symptoms at baseline, which may include night sweats, pruritis, abdominal discomfort, pain under the ribs, bone or muscle pain, and inactivity. MF symptoms observed at baseline are graded on a 10-point scale. Finally, all patients enrolled must have had a platelet count of at least 50 x 109/L in the 4 weeks prior to screening.

Once enrolled and while receiving a stable dose of ruxolitinib, patients in 1 arm of the study received the addition of parsaclisib at 10 mg or 20 mg once daily for 8 weeks and the same dosage once weekly in the weeks following. In a second arm, parsaclisib was administered at 5 mg or 20 mg once daily for 8 weeks and 5 mg once daily thereafter. On treatment with ruxolitinib and a parsaclisib add-on, patients were evaluated for the primary end point of change in spleen volume from baseline to week 12, which was determined by imaging. In addition, change in spleen volume from baseline to week 24, change in spleen length from baseline to each visit, total symptom score (TSS) from baseline to weeks 12 and 24, and safety determined by the number of patient with adverse events (AEs).

A total of 53 patients were included in the study, 10 of whom were evaluated in the safety run-in portion and 43 of whom were randomized to receive ruxolitinib plus 10 mg to 20 mg parsaclisib or ruxolitinib plus 5 mg to 20 mg parsaclisib. Thirty-three patients were dosed daily and weekly, and 20 received all daily dosing. As of the data cutoff date, 82% of patients who received both daily and weekly discontinued treatment in the study compared with 40% in the daily only group. Treatment was ongoing in 6 patients who were being treated on a daily and weekly schedule and 12 of those being treated on a daily-only schedule.

The study population had a median age of 66 years (range, 41-89 years) at baseline and was predominantly male (47%). The median time since the initial diagnosis of MF was 31.2 months (range, 4.9-268.9 months), and the duration of prior ruxolitinib in patients was a median of 18 months (range, 4.8-94 months). Ninety-eight percent of patients had palpable spleen which measured a median of 13.5 cm (range, 5-30 cm). Median spleen volume at baseline was 1995 cm3 (range, 327-5324 cm3). According to the MPN Symptoms Assessment Form, the median TSS in patients at baseline was 25.5 (range, 0-69), and according to the Myelofibrosis Symptoms Assessment Form, the median baseline TSS was 12.9 (range, 0-47).

Hemoglobin levels assessed a baseline showed a median of 101 g/L (range, 63-159 g/L).

Patients presented with several different MF subtypes including primary MF (PMF), post-polycythemia vera MF (PPV-MF), and post-essential thrombocythemia (PET-MF).

In terms of efficacy, patients who received all daily parsaclisib had a higher SVR compared with those treated daily and weekly. A -15.4% reduction was achieved in patients treated daily compared with a -2.3% reduction in spleen volume in those in the daily/weekly group. Then, at 24 weeks, the daily group showed a -25.4% SVR compared with a -2.5% reduction in the daily/weekly group.

“Patients who received all daily parsaclisib dosing demonstrated a continued reduction in splenic length up to 24 weeks. By contrast, patients receiving the daily parsaclisib dosing appeared to plateau after switching to weekly dosing at week 8,” said Abdulraheem Yacoub, MD, associate professor of Medicine, University of Kansas Medical Center, during the AACR poster presentation.

By week 24, 18 patients in the daily/weekly parsaclisib dosing group had palpable spleen compared with 3 in the daily dosing group.

Yacoub also explained that a higher percentage of patients who received all daily dosing demonstrated improvement in symptoms at 12 and 24 weeks. At week 12, there was a 50% or greater symptom reduction in 31% of the all-daily dosing population versus 15% of the daily/weekly dosing population, and at 24 weeks, the same symptom reduction was observed in 17% versus 4%, respectively.

The safety results also favored the daily dosing schedule over the daily/weekly schedule. Overall, the majority of the hematologic treatment-emergent AEs (TEAEs) were grade 1 or 2 in severity. The most common any-grade hematologic TEAEs observed in the all-daily dosing group were cough (25%) and nausea (20%). In the daily/weekly dosing group, the most common any-grade hematologic TEAEs were diarrhea, nausea, and fatigue, which occurred in 33%, 30%, and 30% of patients, respectively.

At least 2% of patients in the study experienced serious TEAEs which included urinary tract infection in 3 patients, and pneumonia, pyrexia, and fall in 2 patients each. AEs were fatal for 1 patient who received all daily dosing and 6 treated daily/weekly. New onset of grade 3 thrombocytopenia was observed in 30% of patients in the all-daily dosing population versus 18% with daily/weekly dosing. No patients who received all daily dosing had new-onset grade 4 thrombocytopenia compared with 21% of the daily/weekly group.

Notably, hemoglobin levels in all study subjects remained stable during the study and there were no cases of anemia. Also, in the daily dosing-only group, there was no colitis, grade 2 or higher diarrhea, or rash. One AE of special interest in the all-daily dosing group was varicella-zoster virus infection, which occurred in only 1 patient. AEs of special interest among patients treated daily/weekly were grade 2 or greater diarrhea in 4 patients, elevated liver function tests in 2 patients, grade 2 or greater rash in 1 patient, and varicella-zoster virus infection in 1 patient.

Grade 3/4 AEs were rare overall, and the AEs commonly observed with PI3K inhibitors were infrequent after adding parsaclisib to ruxolitinib.

Results from the study lead to the development of a phase 3 study exploring parsaclisib as an add-on to ruxolitinib or in combination with ruxolitinib as frontline treatment of patients with MF (NCT04551053).

Yacoub A, Wang ES, Rampal RR, et al. Addition of parsaclisib (INCB050465), a PI3Kδ inhibitor, in patients with suboptimal response to ruxolitinib: A phase 2 study in patients with myelofibrosis. Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT162.

Adding parsaclisib to the ruxolitinib treatment of patients with myelofibrosis who had a suboptimal response on a standard dose of ruxolitinib alone led to improvements in spleen volume reduction and symptom burden.