Caroline Seymour

-mutant non–small cell lung cancer (NSCLC) and brain metastases, oral osimertinib (Tagrisso) achieved rapid, high, and uniform brain exposure which was followed reduction in total brain metastases volume, according to results from the phase 1 ODIN-BM study (NCT03463525).

C]osimertinib given during the 2020 World Conference on Lung Cancer Singapore showed that in terms of [

C]osimertinib uptake, uniform brain distribution of osimertinib was recorded in all patients at all 3 time points with PET exams after intravenous (IV) microdose administration (n = 4). MRI also illustrated reductions in total brain metastases volume (range, 55%-95%) after 3 to 4 weeks of treatment with oral [

C]osimertinib (Tagrisso). T1-weighted MRI scans also illustrated tumor reductions after 35 days of treatment with oral osimertinib in 1 patient.

These data support uniform brain distribution of osimertinib in patients with NSCLC and brain metastases,” wrote the study authors in a presentation of the data.

Central nervous system (CNS) metastases occur in 40% to 50% of patients treated with first- or second-generation EGFR TKIs within 3 years of diagnosis and are associated with poor prognosis and quality of life in patients with NSCLC.

C]osimertinib is a potent and selective third-generation, irreversible, oral EGFR TKI that inhibits 

 T790M. The agent is approved for use as a frontline treatment for patients with metastatic 

-mutant NSCLC and as adjuvant treatment following tumor resection in patients with EGFR-mutant NSCLC.

In the phase 3 AURA3, FLAURA, and ADAURA trials, osimertinib demonstrated systemic and CNS activity in patients with 

-mutant NSCLC. PET studies in healthy participants have also demonstrated comparable blood-brain barrier penetration and brain exposure between [

In the open-label, single-center study, patients underwent 3 PET exams following an IV microdose injection of less than 10 μg of osimertinib at baseline (PET1, day 1), 6 hours after the first dose of 80 mg of oral osimertinib (PET2, days 2-8), and 21 days after daily osimertinib treatment (PET3, days 22-29).

C]osimertinib IV microdoses were administered 6 hours after oral administration of osimertinib to fall within the median Tmax of the oral dose.

Change in volume from baseline, measured on high resolution contrast enhanced T1 MRI scans, was used to evaluate the treatment effect of osimertinib in brain metastases at baseline and day 25 to 35.

MRI-detected brain metastases were also subject to computer-assisted manual delineation into tumor shell (mass) and total tumor, including the core volume.

Following the study period, patients were allowed to continue oral osimertinib until the drug was no longer effective or discontinue treatment.

C]osimertinib in brain metastases at baseline (PET1) and change in PET signal after single (PET2) and multiple (PET3) administrations of oral osimertinib served as the primary end points of the study.

The evaluation of the pharmacokinetics of osimertinib and its metabolite AZ5104 after multiple administrations of oral osimertinib served as a secondary end point of the study.

The safety and tolerability of multiple oral administrations of osimertinib, the effect of osimertinib on brain metastases according to RECIST v1.1 criteria and volumetric analyses using brain MRI, and the treatment effect in extracranial regions using CT were also evaluated.

Eligible patients included adults 18 years or older, with a World Health Organization status of 0 to 2, a minimum life expectancy of 12 weeks, a histological or cytological confirmation of NSCLC, and MRI-confirmed CNS metastases. Patients were also required to be naïve to an EGFR TKI with local or central confirmation of an 

 mutation, or have progressed on a prior EGFR TKI with a confirmed 

 T790M mutation and documented radiological disease progression on immediate prior therapy.

Patients were excluded from enrollment if they had received an EGFR TKI within 10 days, or at least 5 times the half-life, or radiotherapy within 1 week of first osimertinib administration. Treatment with any cytotoxic chemotherapy, investigational agents, or other anticancer drugs within 14 days of first osimertinib administration, and prior osimertinib administration in the present study was not allowed.

Of 35 eligible patients, 10 provided informed consent, 6 of whom failed screening. The remaining 4 patients completed all study treatment and imaging assessments.

C]osimertinib was recorded in healthy brain tissue and brain metastases in all 3 PET exams, regardless of administration of oral osimertinib. [

C]osimertinib volume of distribution (VT) was comparable in brain metastases and healthy brain tissue at baseline.

C]osimertinib-derived signal distribution between brain PET scans across the study were negligible, despite differences in plasma concentrations of cold osimertinib,” wrote the study authors. “This suggests that the [11C]osimertinib PET signal predominantly constitutes non-displaceable binding.”

C]osimertinib in the brain were achieved 11 to 42 minutes (Tmax) after IV injection, with a mean exposure of 1.5% (standard deviation, 0.1%) of injected radioactivity. Whole brain radioactivity was sustained over the scan duration of approximately 90 minutes following Tmax.

Regarding pharmacokinetics, the steady-state mean systemic exposure to metabolite AZ5104 was approximately 13% compared with the parent compound osimertinib.

“Orally administered osimertinib was steadily absorbed into the systemic circulation and slowly eliminated with a flat pharmacokinetic profile across dosing intervals at steady-state,” wrote the authors.

The safety and tolerability data for osimertinib were consistent with the known safety and tolerability profile of the TKI.

Ekman S, Cselényi Z, Varrone A, et al. A PET and MRI study exploring osimertinib brain exposure and efficacy in EGFRm NSCLC CNS metastases. Presented at: 2020 World Lung Conference on Lung Cancer Singapore; January 28-31, 2021; Virtual. Poster P76.72.

Articles

In with EGFR-mutant non–small cell lung cancer and brain metastases, oral osimertinib achieved rapid, high, and uniform brain exposure which was followed reduction in total brain metastases volume, according to results from the phase 1 ODIN-BM study.

Osimertinib Penetrates Blood-Brain Barrier and Decreases Metastasis in EGFR+ NSCLC

Patritumab deruxtecan (U3-1402) demonstrated early and clinically meaningful activity in pretreated patients with metastatic or unresectable 

-mutant non–small cell lung cancer (NSCLC) in the results of a phase 1 trial (NCT03260491) that were presented during the International Association for the Study of Lung Cancer's 2020 World Conference on Lung Cancer Singapore.

The HER3-directed antibody-drug conjugate (ADC) also had a manageable safety profile at the 5.6-mg/kg dose. 

-mutant NSCLC from the dose-escalation and dose-expansion portions had been treated with patritumab deruxtecan, 56 of whom were evaluable for response.

The confirmed objective response rate per blinded independent central review was 25% (n = 14; 95% CI, 14.4%-38.4%), which consisted of a 2% complete response rate (n = 1) and a 23% partial response rate (n = 13). The stable disease rate was 45% (n = 25).

“Early antitumor activity was observed in this heavily pretreated patient population, with a median follow-up time of 5 months,” wrote Helena A. Yu, MD, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center and colleagues in a presentation of the data. “These data support further clinical investigation of this HER3-directed ADC in a patient population with no available targeted therapy treatments.”

-mutant NSCLC and overexpression is associated with poor outcomes.

Patritumab deruxtecan is a novel HER3-directed ADC that consists of the monoclonal antibody patritumab, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload.

The phase 1 study was comprised of a dose-escalation and dose-expansion phase. In the dose-escalation phase, patients with metastatic or unresectable 

-mutant NSCLC who had progressed on osimertinib (Tagrisso) or were T790M negative after progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) received 5.6 mg/kg of patritumab deruxtecan every 3 weeks. In the dose-expansion cohort, patients with metastatic or unresectable 

-mutant NSCLC who had received at least 1 prior EGFR TKI and at least 1 prior platinum-based chemotherapy regimen received 5.6 mg/kg of patritumab deruxtecan every 3 weeks.

Evaluation of the antitumor activity of patritumab deruxtecan served as the primary end point of the study. The safety and tolerability of the agent were evaluated as secondary end points.

Patients had a median of 4 prior lines of therapy for advanced or metastatic disease (range, 1-9). Prior therapies included osimertinib (n = 49; 86%), another EGFR targeted therapy (n = 3; 5%), platinum-based chemotherapy (n = 51; 90%), and anti–PD-1/PD-L1 therapy (n = 23; 40%).

Approximately half of patients (n = 27; 47%) had a history of central nervous system metastases.

Additional data indicated that the disease-control rate was 70% (n = 39; 95% CI, 55.9%-81.2%). The median time to response was 2.0 months (range, 1.2-2.8), and the median duration of response was 6.9 months (range, 3.0-7.0).

In terms of safety, patritumab deruxtecan continued to demonstrate a manageable safety profile. The most common grade 3 or greater treatment-emergent adverse effects (TEAEs) were thrombocytopenia (n = 16; 28%) and neutropenia (n = 11; 19%).

TEAEs associated with drug discontinuation (9%) included fatigue (n = 2), decrease appetite (n = 1), interstitial lung disease (ILD; n = 1), pneumonitis (n = 1), and upper respiratory tract infection (n = 1). No discontinuations were attributed to thrombocytopenia or neutropenia.

Three (5.3%) ILD events were determined to be related to treatment by an independent central review committee. No treatment-related TEAEs were associated with death.

An exploratory biomarker analysis, which was also presented during the meeting, reported that almost all evaluable patient tumors (n = 43) expressed membrane HER3 at baseline. The median membrane H score was 180 (range, 2-280) out of 300.

Moreover, heterogenous EGFR TKI resistance mechanisms were identified in patients’ pretreatment tumor tissue and circulating tumor DNA (ctDNA). Clinical responses were reported in patients with diverse TKI resistance mechanisms, including 

All examined patient samples showed a reduction in 

-activating mutations in ctDNA following treatment with patritumab deruxtecan. Patients who experienced a confirmed clinical response were more likely to have ctDNA clearance of 

-activating mutations at week 3 or week 6. Failure to clear 

-activating mutations in ctDNA was associated with a best overall response of progressive disease.

“These data provide important insights about how a HER3-directed therapy may interact in previously treated NSCLC tumors with diverse mechanisms of EGFR TKI resistance, including mechanisms not directly related to EGFR,” said Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute.3 “While an association between higher levels of HER3 expression and clinical activity was seen with patritumab deruxtecan, additional analyses from this study and additional studies are needed to better understand the role of HER3 expression alone in the optimal selection of patients.”

The phase 2 HERTHENA-Lung01 study (NCT04619004) is planned to launch in early 2021 and will evaluate single-agent patritumab deruxtecan in patients after failure of EGFR TKIs and platinum-based chemotherapy.4

1. Helena YA, Baik C, Gold K, et al. Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract OA03.04.

2. Jänne PA, Baik C, Hayashi H, et al. Dynamics of molecular markers in EGFR-mutated NSCLC patients treated with patritumab deruxtecan (HER3-DXd; U3-1402). Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Poster P01.04

3. New biomarker analyses from patritumab deruxtecan phase 1 study in patients with EGFR-mutated NSCLC presented at WCLC 2020. News release. Business Wire. January 29, 2020. Accessed January 29, 2021. https://bwnews.pr/3prQbLM.

4. Jänne PA, Johnson ML, Goto Y, et al. HERTHENA-Lung01: a randomized phase 2 study of patritumab deruxtecan (HER3-DXd; U3-1402) in previously treated metastatic EGFR-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Poster P01.01.

Patritumab deruxtecan demonstrated early and clinically meaningful activity in pretreated patients with metastatic or unresectable EGFR-mutant non–small cell lung cancer in the results of a phase 1 trial that were presented during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer Singapore.

Patritumab Deruxtecan Shows Early Activity in Metastatic EGFR-Mutant NSCLC

Improved antitumor activity of the triplet combination of urelumab, a GVAX vaccine, and nivolumab (Opdivo) was observed in patients with resectable pancreatic ductal adenocarcinoma (PDAC), according to findings from a 3-arm phase 1/2 trial (NCT02451982) that were presented during the 35th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2020). Specifically, a 30% pathologic response rate and a mild toxicity pro-file for the triplet was also observed in the trial. 

The 3 pathologic responses were moderate per the College of American Pathologists grade 2 criteria. Nine patients remain disease free after a median follow-up of 12 months.

“[This is a] preliminary sign of the antitumor efficacy [of the regimen],” wrote Lei Zheng, MD, PhD, lead author, and professor of oncology and surgery and codirector, Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins University School of Medicine in the poster. “The immune and clinical efficacy of anti-CD137 agonist-based combinations war-rant further investigation.” 

The GVAX vaccine is an allogeneic pancreatic cancer cell vaccine that expresses granulocyte-macrophage colony-stimulating factor. The off-the-shelf product, produced at Johns Hopkins University Good Manufacturing Practice, is safe but has modest activity as a single agent.

Urelumab is a fully human anti-CD137 agonist immunoglobulin G4 monoclonal antibody. In mouse models, the immune costimulatory molecule CD137 within the tumor microenvironment remained inactivated after vaccine-induced T-cell and PD-1 inhibition. Supported by additional preclinical studies, investigators theorized that the addition of urelumab could provide synergistic benefit.

The trial consists of 3 arms: GVAX alone (arm A), GVAX plus nivolumab (arm B), and GVAX plus nivolumab and urelumab (arm C).

Eligible patients were at least 18 years of age, had R0/R1 resection, radiographic evidence of resectable pancreatic ductal adenocarcinoma, no prior anticancer treatment, no active autoimmune disease, and adequate hematologic, renal, and hepatic functions.

An increase in intratumoral CD137-positive and CD8-positive T cells served as the primary objective of the study. Evaluation of safety, overall survival, disease-free survival, and other immune parameters served as secondary end points.

 of cyclophosphamide intravenously (IV) on day 0 and 5 × 10

 cells of the GVAX vaccine intradermally on day 1 two weeks prior to surgery, 6 to 10 weeks following surgery, and every 4 weeks for 4 cycles after adjuvant chemotherapy.

 of cyclophosphamide and 480 mg of IV nivolumab on day 0 and 5 × 108 cells of the GVAX vaccine intradermally on day 1, two weeks prior to surgery, 6 to 10 weeks following surgery, and every 4 weeks for 4 cycles after adjuvant chemotherapy.

In arm C, patients received IV nivolumab at a dose of 480 mg plus 8 mg of IV urelumab and 200 mg/m

 of IV cyclophosphamide on day 0, two weeks prior to surgery, 6 to 10 weeks following surgery, and every 4 weeks for 4 cycles after adjuvant chemotherapy. The GVAX vaccine was administered intradermally on day 1.

Between February 2019 and August 2020, 10 evaluable patients were enrolled and under-went R0 resection. All 10 patients received at least 2 cycles of the study regimen. Toxicities were mild and consisted of grade 1 vomiting (n=2),fatigue (n=4), flu-like symptoms (n=2), arthritis (n=1), grade 1/2 nausea (n=7), periorbitaledema without pruritus around the eyes (n=1),and grade 2 abdominal pain (n=1), anorexia(n=1), diarrhea (n=1), thyroiditis (n=1), pruritus (n=3), peripheral sensory neuropathy (n=1), and increased liver function tests (n=1).Two cases of grade 3 rash were also reported, which responded quickly to oral steroids and did not recur after redosing.

“Previous observations of liver toxicity with urelumab or other T-cell agonists and severe immune-related adverse effects were not observed in this trial, suggesting urelumab is safe as neoadjuvant/adjuvant therapy in this resectable PDAC patient population,” concluded the study authors.

Zheng L, Judkins C, Hoare J, et al. Urelumab (anti-CD137 agonist) in com-bination with vaccine and nivolumab treatments is safe and associated with pathologic response as neoadjuvant and adjuvant therapy for resect-able pancreatic cancer. Poster presented at: Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting & Pre-Conference Program; November 9-14, 2020; virtual. Abstract 812.


Improved antitumor activity of the triplet combination of urelumab, a GVAX vaccine, and nivolumab was observed in patients with resectable pancreatic ductal adenocarcinoma, according to findings from a 3-arm phase 1/2 trial.

Urelumab Combo Leads to Improved Pathologic Response in Resectable PDAC

Rate for objective response and stable disease were encouraging, according to findings from a phase 2 trial (NCT03132636) evaluating the PD-1 inhibitor, cemiplimab-rwlc (Libtayo). This antitumor activity included responses that were durable and safe in patients with metastatic basal cell carcinoma (mBCC) after progression on or intolerance to hedgehog inhibitors. Interim results were presented ahead of the 35th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2020).

Among 28 patients, the objective response rate (ORR) per independent central review (ICR) was 21.4% (n = 6; 95% CI, 8.3%-41.0%), which consisted of all partial responses (PRs). The stable disease (SD) rate was 35.7% (n =10), which translated to a disease control rate (DCR) of 67.9%, defined as the proportion of patients with complete response (CR), PR, SD, or nonprogressive disease at first assessment (95% CI, 47.6%-84.1%) (

“There have been case reports with cemiplimab, but this is the first prospective study in any meaningful number of patients. The activity and durability [of the agent] seem to be promising,” Karl Lewis, MD, lead study author and professor of medicine-medical oncology at the Colorado School of Medicine, said in a virtual press briefing ahead of SITC 2020, which was held virtually.

Basil cell carcinoma (BCC) is the most common type of skin cancer, and ultraviolet exposure is a significant risk factor. The majority of patients with advanced BCC undergo curative surgery. However, systemic therapy is also available for patients with advanced disease who are ineligible for curative surgery or radiation.

Vismodegib (Erivedge) and sonidegib (Odomzo) are oral hedgehog inhibitors approved for patients with locally advanced or mBCC. However, no FDA-approved treatment options are available to patients who progress on or are intolerant to hedgehog inhibitors.

Cemiplimab is the first systemic therapy that has shown clinical benefit in patients with locally advanced and mBCC after treatment with hedgehog inhibitors. The first demonstration was reported in findings from the locally advanced cohort of this phase 2 study presented during the European Society for Medical Oncology Virtual Congress 2020.

The phase 2 study enrolled 2 cohorts: group 1 con-sisted of patients with nodal and distant mBCC and group 2 of patients with locally advanced BCC (n=84).The mBCC cohort included patients followed for approx-imately 57 weeks to provide an ORR with a 95% CI.

Patients received 350 mg of intravenous cemiplimab every 3 weeks for up to 93 weeks. Tumor assessments were performed from days 1 to 5 every 9 weeks and from days 6 to 9 every 12 weeks thereafter. Tumor response assessment was measured by ICR using RECIST 1.1 criteria for visceral lesions or modified World Health Organization criteria for skin lesions.

ORR per ICR served as the primary end point of the study. Secondary end points included ORR by investi-gator review, progression-free survival (PFS), PFS by ICR and investigator review, overall survival, CR rate by ICR, and safety and tolerability of cemiplimab.

Regarding prior therapy in the mBCC cohort, 100% of patients received vismodegib (n=28),10.7% (n=3) received sonidegib (Odomzo), and 10.7% (n=3) received vismodegib and sonidegib.Reasons for discontinuation of prior therapy includ-ed disease progression on hedgehog inhibitor therapy (75.0%; n=21); prior hedgehog inhibitorintolerance (35.7%; n=10), predominantly forvismodegib (39.3%; n=11) versus sonidegib (7.1%; n=2); and SD as best response after 9 months on hedgehog inhibitor therapy (17.9%; n=5).

Twenty-five percent of patients (n=7) experi-enced progressive disease. Less than 10% of patients (7.1%; n=2) were not evaluable.

The median duration of response (DOR) had not been reached at the time of data cutoff. The 6- and 12-month DOR estimates for patients with response were 100% (95% CI, 68.3%-97.6%) and 66.7% (95% CI, 19.5%-90.4%), respectively.

The safety profile of cemiplimab was found to be consistent with prior reports of the agent in other tumor types. Any-grade treatment-related adverse effects (TRAEs) occurred in 78.6% of patients (n=22). Grade 3 or higherTRAEs were reported in 17.9% of patients (n=5), and 1 death from staphylococcal pneu-monia occurred, which was determined to be unrelated to study treatment.

 The most common TRAEs were fatigue (25%; n=21), pruritus (14%; n=12), and asthenia(14%; n=12). The most common grade 3 orhigher TRAEs were fatigue (2%; n=2), colitis (2%; n=2), and autoimmune colitis (2%; n=2).Fourteen patients (17%) discontinued treatment due to any-grade TRAEs.

In previously presented findings of the locally advanced BCC cohort, cemiplimab led to an ORR of 31.0% (95% CI, 21.3%-42.0%), which included a 6% CR rate (n=5) and a 25.0% PR rate (n=21). Additionally, slightly less than half of patients (48.8%; n=41) achieved SD.

"In the locally advanced cohort, responses to [cemiplimab] seemed to be delayed. Unlike cuta-neous squamous cell carcinoma, for which cemi-plimab is approved [and] patients that respond seem to respond quickly, [there seems to be a time lag for] patients with basal cell carcinoma....Hopefully, with longer follow-up, this [21.4%] response rate might improve,” Lewis said.

In the locally advanced cohort, the median DOR per ICR had not been reached at the time of data cutoff. The 6- and 12-month DOR rates were 90.9% (95% CI, 68.3%-97.6%) and 85.2% (95% CI, 60.5%-95.0%), respectively.

Mario Sznol, MD, professor of medicine at Yale School of Medicine and comoderator of the press briefing, offered some perspective on the study, stating, “This is really an important advance for these patients. [As we know], any new therapeutic has substantial clinical significance.”

Lewis KD, Peris K, Sekulic A, et al. Interim analysis of phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma (mBCC) who progressed on or are intolerant to hedgehog inhibitors (HHIs). Poster presented at: Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting & Pre-Conference Programs; November 9-14, 2020; Virtual Abstract 428.

Rate for objective response and stable disease were encouraging, according to findings from a phase 2 trial evaluating the PD-1 inhibitor, cemiplimab-rwlc.

Caroline Seymour | Authors

Articles

Osimertinib Penetrates Blood-Brain Barrier and Decreases Metastasis in EGFR+ NSCLC

Patritumab Deruxtecan Shows Early Activity in Metastatic EGFR-Mutant NSCLC

Urelumab Combo Leads to Improved Pathologic Response in Resectable PDAC

Durable Responses Are Observed With Cemiplimab in mBCC