The FDA has granted a breakthrough therapy designation to tipifarnib for use in patients with recurrent or metastatic 

-mutated head and neck squamous cell carcinoma (HNSCC) with variant allele frequency (VAF) of 20% or higher following progressive disease on platinum-based chemotherapy.1

The decision is based on findings from the phase 2 RUN-HN trial (KO-TIP-001; NCT023383927) presented during the 2020 ASCO Virtual Scientific Program, in which tipifarnib elicited an objective response rate (ORR) of 50.0% (95% CI, 26.0%-74.0%) in response-evaluable patients with 

“We are very pleased that the FDA has awarded breakthrough therapy designation to tipifarnib, and we appreciate the agency’s affirmation of its potential to treat this devastating disease,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, stated in a press release. “We remain focused on conducting our AIM-HN registration-directed trial and look forward to working closely with the FDA to bring this therapy to patients as soon as possible.”

The trial enrolled patients with solid tumors that harbored 

 mutations. The first stage of the trial comprised 2 cohorts: patients with thyroid cancer (n = 13) and patients with a solid tumor other than thyroid cancer (n = 13).

For the second stage of the trial, those in cohort 2 who had HNSCC moved into a HNSCC extension cohort, which could enroll up to 30 patients. Cohort 3 was also added, and this would enroll up to 20 patients with tumors other than HNSCC. Here, patients had to have a 35% or higher 

 VAF with serum albumin of 3.5 g/dL or higher.

To be eligible for enrollment, patients could not have any curative therapeutic option available to them, they had to have a tumor harboring a 

 mutation, measurable disease per RECIST v1.1 criteria, and an ECOG performance status of either 0 or 1.

In the second stage of the trial, patients were given oral tipifarnib at a twice-daily dose of 600 mg on days 1 through 7 and days 15 through 21 as part of 28-day treatment cycles.

The primary end point of the trial was ORR achieved with tipifarnib, while the secondary end point was safety and tolerability. Investigators examined progression-free survival (PFS) and duration of response (DOR) as exploratory end points.

A total of 21 patients were enrolled to the trial at the time of the presentation and 20 of them received treatment. Eighteen patients were determined to be evaluable for efficacy. The median age of study participants was 64 years, 66.7% were male, and in 52.4%, the primary tumor location was the oral cavity. Patients received a median of 2 previous anticancer regimens, and these treatments included platinum-based chemotherapy (90.5%), immunotherapy (61.9%), and cetuximab (Erbitux; 52.4%). Approximately 30% of patients were positive for human papillomavirus.

Additional results revealed that the median DOR with tipifarnib was 14.7 months. Moreover, the median PFS with the agent was 5.9 months (95% CI, 3.5-19.2), and the last previous line of treatment was 2.8 months (95% CI, 1.1-5.2). The median overall survival reported with tipifarnib was 15.4 months (95% CI, 7.0-46.4).

Tipifarnib is also under examination in the international, multicenter, open-label, 

 (KO-TIP-007; NCT33719690) in patients with 

-mutated HNSCC. Investigators seek to determine the ORR of tipifarnib in these patients; they will also retrospectively evaluate how the ORR to frontline treatment compares between the accrued patients with 

-mutated disease and matched-case control patients with 

The agent is also examination in patients with 

-mutated urothelial carcinoma (IST-01; NCT025335650).

Kura Oncology receives FDA breakthrough therapy designation for tipifarnib in head and neck squamous cell carcinoma. News release. Kura Oncology, Inc. February 24, 2021. Accessed February 24, 2021. 

Ho AL, Hanna GJ, Scholz CR, et al. Preliminary activity of tipifarnib in tumors of the head and neck, salivary gland and urothelial tract with HRAS mutations. 

. 2020;38(suppl 15):6504. doi:10.1200/JCO.2020.38.15_suppl.6504

This article was originally published on OncLive as, "

FDA Grants Breakthrough Therapy Designation to Tipifarnib for HRAS-Mutated HNSCC

Articles

The FDA has granted a breakthrough therapy designation to tipifarnib for use in patients with recurrent or metastatic HRAS-mutated head and neck squamous cell carcinoma with variant allele frequency of 20% or higher following progressive disease on platinum-based chemotherapy.

Tipifarnib Gets Breakthrough Therapy Designation for HRAS-Mutated HNSCC

The FDA has approved the PD-L1 IHC 22C3 pharmDx assay, developed by Agilent Technologies Inc, for expanded use in patients with non–small cell lung cancer (NSCLC).

The assay can now be utilized to help identify patients who may be candidates for treatment with 

cemiplimab-rwlc (Libtayo), which was granted FDA approval

 on February 22, 2021, for use as a single agent in the first-line treatment of patients with advanced NSCLC who have a PD-L1 tumor proportion score of 50% or higher.

The regulatory decision was based on findings from an analysis of 710 patients with a PD-L1 expression of 50% or higher who were randomized to receive cemiplimab in the phase 3 EMPOWER-Lung 1 trial (NCT033088540). Here, the agent resulted in a 32% reduction in the risk of death compared with chemotherapy. Specifically, the median overall survival (OS) in the investigative arm was 22 months versus 14 months with chemotherapy (HR, 0.68; 95% CI, 0.53-0.87; 

Moreover, the median progression-free survival (PFS) with cemiplimab was 6.2 months per blinded independent central review compared with 5.6 months with chemotherapy (HR, 0.59; 95% CI, 0.49-0.72; 

The survival benefit associated with cemiplimab was reported across all subgroups evaluated in the trial, with the exception of OS in female patients.

“Anti–PD-1 therapies, including [cemiplimab], continue to broaden the potential for the treatment of patients across different cancer types,” Sam Raha, president of Agilent’s Diagnostics and Genomics Group, stated in a press release. “With the FDA approval of PD-L1 IHC 22C3 pharmDx as a companion diagnostic for treatment with [cemiplimab] monotherapy in advanced NSCLC, Agilent further strengthens its ability to elevate pathologist confidence in reporting results to oncologists and bolsters our role as a global pioneer in developing companion diagnostics for targeted treatments.”

The multicenter, open-label, phase 3 trial evaluated cemiplimab monotherapy compared with investigator’s choice of platinum-doublet chemotherapy in the frontline treatment of patients with advanced NSCLC whose tumors had a PD-L1 expression of at least 50%. The PD-L1 IHC 22C3 pharmDx was used to examine PD-L1 status in those enrolled to the trial. PD-L1 expression was evaluated in formalin-fixed, paraffin-embedded tumor samples at a central laboratory.

To be eligible for inclusion, patients had to be aged 18 years or older, have histologically or cytologically confirmed stage IIIB or IIIC or stage IV squamous or nonsquamous NSCLC with a PD-L1 expression of at least 50%, and ECOG performance status of 0 or 1, adequate bone marrow and organ function, as well as at least 1 measurable lesion per RECIST v1.1 criteria.

Patients who were never smokers or who had active or untreated brain metastases were excluded. Moreover, if patients had tumors that harbored 

 fusions, they could not participate. Anyone with active, known, or suspected autoimmune disease that needed systemic treatment within the previous 2 years or who had uncontrolled hepatitis B or C infection or human immunodeficiency virus, did not participate.

The primary end points of the trial included OS and PFS, while secondary end points comprised objective response rate (ORR), duration of response, health-related quality of life, and safety with cemiplimab versus chemotherapy. The pharmacokinetics and immunogenicity of the agent is also under exploration.

A total of 3662 patients were screened for the trial and 720 patients met the eligibility criteria. Notably, 74% of patients who experienced disease progression on chemotherapy were given cemiplimab as a crossover treatment. Thirty-two percent of patients who had progressive disease on cemiplimab went on to receive extended treatment with the addition of chemotherapy.

A total of 563 patients comprised the population of patients who had a PD-L1 expression of 50% or higher. The median age of these patients was 63.5 years and just under half, or 46.5%, were aged 65 years or older. Moreover, 85.5% were male, 76.5% were from Europe, and 73% had an ECOG performance status of 1. Additionally, 65% of patients were past smokers, 57% had nonsquamous histology, and 12% had brain metastases.

In this population, the overall median duration of follow-up was 10.8 months for cemiplimab and 10.9 months for chemotherapy. Just under half, or 46%, of patients were still receiving cemiplimab and 16% of patients were still receiving chemotherapy at the time of data cutoff.

The intent-to-treat (ITT) population (n = 710) was comprised of the 563 patients with a PD-L1 of at least 50% and a total of 56 patients who definitively had a PD-L1 expression of less than 50%. The overall median duration of follow-up with cemiplimab and chemotherapy was 13.1 months each.

In the ITT population, cemiplimab also demonstrated an improvement in OS versus chemotherapy, at 22.1 months (95% CI, 17.7–not evaluable) and 14.3 months (95% CI, 11.7-19.2), respectively (HR, 0.68; 95% CI, 0.53-0.87; 

= .0022). Cemiplimab was also found to improve PFS compared with chemotherapy, at a median of 6.2 months (95% CI, 4.5-8.3) versus 5.6 months (95% CI, 4.5-6.1), respectively (HR, 0.59; 95% CI, 0.49-0.72; 

Twenty-eight percent of the 355 patients who received cemiplimab experienced grade 3/4 treatment-emergent adverse effects (TEAEs), and pneumonia (5%) was the most commonly reported effect, followed by anemia (3%), and hyponatremia (3%). Grade 3/4 TEAEs were observed in 39% of those who received chemotherapy; anemia was experienced by 16% of patients, neutropenia presented in 10%, and thrombocytopenia occurred in 8%.

Agilent PD-L1 IHC 22C3 pharmDx receives expanded FDA approval in non-small cell lung cancer (NSCLC). News release. Agilent Technologies Inc. February 22, 2021. Accessed February 23, 2021. 

Sezer A, Kilickap S, Gümüs M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. 

. 2021;397(10274):592-604. doi:10.1016/S0140-6736(21)00228-2

FDA Approves Companion Diagnostic for Cemiplimab in NSCLC

The FDA has approved the PD-L1 IHC 22C3 pharmDx assay, developed by Agilent Technologies Inc, for expanded use in patients with non–small cell lung cancer.

FDA Approves Companion Diagnostic for Cemiplimab in Lung Cancer

The National Comprehensive Cancer Network (NCCN) has issued guidelines for the management of children with a rare type of kidney cancer referred to as Wilms Tumor, or nephroblastoma.

The document highlights evidence-based recommendations for how to maximize benefits while minimizing toxicities in this patient population. Notably, the guidance comprises critical information for providers who treat pediatric tumors, hematologic malignancies, and other blood disorders that may be encountered relatively infrequently. The guidelines also contain diagnostic information for primary care pediatricians to ensure that the cancer is identified early and managed in a way that results in fewer toxicities for the patients.

“Keeping up with all of the current literature for the broad array of children’s oncologic and hematologic malignancies can be daunting. The NCCN Guidelines for Wilms Tumor provide compiled, annotated, and vetted recommendations for diagnosis, treatment, and follow up—in keeping with NCCN’s goals for streamlining and improving care so that patients can live better lives,” Elizabeth Mullen, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who is also a member of the NCCN Guidelines Panel for Wilms Tumor, stated in a press release.

Wilms tumor is the most common cancer of the kidneys in children and it is known to affect those between the ages of 3 years and 4 years.3 In the majority of patients, the tumor will present in just 1 kidney, although it has been identified in both kidneys at the same time.

One factor that may increase the risk of Wilms tumor is African-American race; these children tend to be at a slightly higher risk for this cancer compared with other races. Additionally, Asian-American children may be at lower risk than children of other races. Another risk factor is having a familial history of the cancer.

Wilms tumor is also known to occur more commonly in children with aniridia or hemihypertrophy at birth; it has also been shown to occur as part of other rare syndromes like WAGR syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome.

“The treatment of Wilms tumor is guided by the results of a series of sequential clinical trials that started back in the 1960s,” Frank M. Balis, MD, professor of pediatrics, Louis and Amelia Canuso Family Endowed Chair for Clinical Research in Oncology, of the Children’s Hospital of Philadelphia/Abramson Cancer Center at the University of Pennsylvania, and chair of the NCCN Guidelines Panel for Wilms Tumor, added in the release. “Treatment approaches have been refined through these clinical trials, making treatment selection more and more complex and nuanced.”

Balis added that treatment decisions should be based on clinical and biological risk factors, the presence of unilateral versus bilateral disease, and patient response to treatment.

NCCN clinical practice guidelines in oncology (NCCN guidelines): Wilms tumor. National Comprehensive Cancer Network. Accessed February 17, 2021.

New NCCN guidelines analyze evidence for cancer type found almost exclusively in children. News release. National Comprehensive Cancer Network. February 17, 2021. Accessed February 17, 2021. 

Wilms’ tumor. Mayo Clinic website. Updated April 24, 2020. Accessed February 17, 2021. 

NCCN Issues First-Ever Guidance for Pediatric Solid Tumor

The National Comprehensive Cancer Network has issued guidelines for the management of children with a rare type of kidney cancer referred to as Wilms Tumor, or nephroblastoma.

NCCN Publishes Guidelines for Pediatric Solid Tumor

The use of next-generation sequencing (NGS) demonstrated that 34% of patients with sarcoma had potentially actionable mutations, according to results from a retrospective analysis shared in a poster presentation during the 2020 Connective Tissue Oncology Society meeting.

In light of the results, treatment decisions for 8% of patients were altered, according to Brian Shulte, a fellow at Northwestern University.

One patient with Ewing sarcoma was found to have 

 loss, and so they were given copanlisib (Aliqopa). Among 2 patients with leiomyosarcoma, 1 patient was found to have an 

 fusion and the other was found to have microsatellite instability–high disease; thus, these patients were given alectinib (Alecensa) and nivolumab (Opdivo), respectively.

Another patient with chondrosarcoma was found to have a tumor that harbored an 

 mutation, so they were administered treatment with ivosidenib (Tibsovo), while another patient with synovial sarcoma was found to have 

 V600E–mutated disease, so they were given encorafenib (Braftovi).

Of 3 patients who had soft tissue sarcoma not otherwise specified (STS NOS) and underwent NGS testing were found to have CDK4 amplification, CCND1 amplification, and a 

 fusion; as a result, the first 2 patients were given palbociclib (Ibrance), while the third patient received larotrectinib (Vitrakvi). One patient with myxofibrosarcoma was found to have high tumor mutational burden, and in light of this, they were administered atezolizumab (Tecentriq).

NGS is increasingly being utilized in the management of patients with sarcoma, although its exact role remains undefined. To gain further insight, investigators launched a retrospective analysis. Here, they set out to examine the use of this testing in this patient population and characterize the effect of the results on clinical decisions. They also wanted to qualify instances in which NGS was used to gain a better understanding on the incidence of mutation within a large population of patients with sarcoma.

Investigators utilized the Northwestern Medicine Oncoset Database to identify certain patients who were seen through the Northwestern Healthcare system, who had a tissue diagnosis of sarcoma and underwent NGS testing. The clinical course was interpreted by the investigators to evaluate the impact of the testing on treatment decisions. Mutations were cross referenced with ongoing tissue agnostic and sarcoma-specific clinical trials.

To be included in the analysis, patients had to be older than 16 years and have a histologically confirmed sarcoma diagnosis and have received NGS testing with the Foundation Medicine assay, the Tempus CDx assay, or the Guardant 360 assay.


A total of 117 patients were evaluated with assays that were performed between 2014 and 2020. The median age of participants was 55 years and 52% were female. One assay was used per patient (range, 1-4). Of the patients included, 31% had leiomyosarcoma, 18% had STS NOS, 11% had angiosarcoma, 9% had liposarcoma, and 31% had other. Among those who were tested with the Guardant assay, 25% did not have variants detected, versus 2% of those who received the Tempus assay.

When looking at the utilization of assays over time, it appears that testing surged in 2019 compare with the other years examined. Among the actionable mutations identified NF1 mutation, 

 amplification were most prevalent, followed by 

Moreover, the incidence of actionable mutations was found to increase over time.

Schulte B, Katam N, Behdad A, et al. Impact of next-generation sequencing (NGS) on the treatment of patients with sarcoma. Presented at: 2020 Connective Tissue Oncology Society meeting; November 18-21, 2020; Virtual. Poster 106. 

Next-Generation Sequencing Reveals Potentially Actionable Mutations in Sarcoma

The use of next-generation sequencing demonstrated that 34% of patients with sarcoma had potentially actionable mutations.



Next-Generation Sequencing Unearths Actionable Mutations in Sarcoma

The FDA has accepted and granted a priority review designation to the biologics license application for Vicineum for use in patients with high-risk Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NMIBC), according to an announcement from Sesen Bio, the developer of the drug.

The regulatory agency will review the application for Vicineum within 6 months, compared with the standard 10 months from the date of the filing. The FDA is not planning to hold an advisory committee meeting to discuss the application; the agency is slated to make its final decision on Vicineum on, or before, August 18, 2021.

“We have been meeting with the FDA regularly for the past 2 years on the application for Vicineum. We understand the FDA’s position and guidance very clearly and have found the review process to be collaborative and engaging,” Thomas Cannell, DVM, president and chief executive officer of Sesen Bio, stated in a press release. “With these critical FDA decisions, we have reached an inflection point for the Company. In addition to a clear regulatory path forward, we have continued to strengthen our balance sheet in preparation for the potential launch of a product we believe represents a significant advancement over available therapies.”

A recombinant fusion protein, Vicineum, was designed to target epithelial cell adhesion molecule–specific antigens on the surface of tumor cells to deliver 

 Exotoxin A, a potent inhibitor of protein synthesis.

The agent is under examination in the open-label, multicenter, single-arm, phase 3 VISTA trial (NCT024492339) as a treatment for patients with NMIBC who had previously received the current standard of care, BCG.

Results showed that among 89 patients with carcinoma 

 with or without papillary disease that was determined to be refractory or recurred less than 11 months following their last course of BCG, the complete response (CR) rate achieved with Vicineum was 40% (95% CI, 330%-51%) at 3 months. At 6 months, the rate was 28% (95% CI, 19%-39%), whereas it was 21% (95% CI, 13%-31%) and 17% (95% CI, 10%-26%) at 9 months and 12 months, respectively.

Although BCG is an effective option for many patients, tolerability and disease recurrence continue to pose a challenge. If the option does not demonstrate efficacy or the patient can no longer receive it, they are recommended to undergo radical cystectomy. Thus, new options are needed for this population.

The trial completed registration in 2018, with 133 patients enrolled across 3 cohorts based on histology and time to disease recurrence following at least 2 courses of BCG with at least 5 doses in the first course and 2 doses in the second course.

To be eligible for enrollment, patients had to have disease that is refractory or has relapsed after BCG treatment, they had to have a Karnofsky performance status of 60 or greater, and acceptable organ function.

If patients were pregnant or breastfeeding, had evidence of urethral or upper tract transitional cell carcinoma within the past 2 years, had hydronephrosis, received any intravesicular or other chemotherapy treatment within 2 weeks or an investigational 4 weeks before initial dose of the study treatment, they were excluded.

Primary efficacy end points of the trial included CR rate and duration of response (DOR) for patients in cohort 1, while secondary end points comprised time to disease recurrence for patients in cohort 3, as well as time to cystectomy, progression-free survival, event-free survival, and overall survival (OS) for patients across all cohorts.

As of the May 29, 2019 data cutoff, the 82 patients with carcinoma 

 with or without papillary disease that was determined to be refractory or recurred within 6 months of their last course of BCG who comprised cohort 1 experienced CR rates of 39%, 26%, 20%, and 17%, at 3 months, 6 months, 9 months, and 12 months, respectively.

Cohort 2 comprised patients with carcinoma 

 with or without papillary disease that was determined to be refractory or recurred after 6 months, but less than or equal to 11 months, following their last course of BCG. Here, the CR rate at 3 months and 6 months was 57%; it was 43% at 9 months and 14% at 12 months.

The median DOR for patients enrolled to cohort 1 was 273 days (95% CI, 122–not applicable [NA]) per the Kaplan–Meier method. Moreover, additional data from an ad-hoc analysis of pooled data for 93 patients in cohorts 1 and 2 showed that among those who experienced a response to treatment at 3 months, 52% achieved a complete response for 12 months or longer following the start of treatment.

High-risk papillary disease was linked with higher rates of progression and recurrence. The median time to disease recurrence in the 40 patients included in cohort 33 was 402 days (95% CI, 170-NA).

Additionally, of all 133 patients who received Vicineum, more than 75% were estimated to continue to be cystectomy free at 2.5 years. Ad-hoc analysis of responders and non-responders for all patient indicated that about 88% of those who responded to treatment were estimated to remain cystectomy free at 3 years.

Ninety percent of all 133 patients who received the agent were estimated to continue to be free of disease progression at 2 years or longer, and 29% of all patients were estimated to remain event free at 12 months. Also, 96% of all patients were estimated to have an OS of 2 years or longer.

Regarding safety, 95% of toxicities experienced by patients across treatment cohorts were grade 1 or 2 in severity. The most frequently reported adverse effects (AEs) associated with treatment included dysuria (14%), hematuria (13%), and urinary tract infection (12%). Toxicities were determined to be manageable and reversible. Only 3% (n = 4) of patients discontinued treatment with Vicineum because of toxicity. Fourteen percent of patients experienced serious AEs (SAEs), irrespective of treatment attribution. Four treatment-associated SAEs were observed in 3 patients and included grade 33 acute kidney injury, grade 2 pyrexia, grade 4 cholestatic hepatitis, and grade 5 renal failure.

Sesen Bio announces FDA acceptance and priority review of its biologics license application for Vicineum. News release. Sesen Bio. February 17, 2021. Accessed February 17, 2021. 

Sesen Bio reports positive, preliminary data update from phase 3 VISTA trial for high-risk non-muscle invasive bladder cancer. News release. Sensen Bio. August 8, 2019. Accessed February 17, 2021. 

Vicinium treatment for subjects with non-muscle invasive bladder cancer previously treated with BCG. ClinicalTrials.gov. Updated October 14, 2020. Accessed February 17, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02449239

FDA Grants Priority Review to Vicineum for High-Risk, BCG-Unresponsive NMIBC

The FDA has accepted and granted a priority review designation to the biologics license application for Vicineum for use in patients with high-risk Bacillus Calmette-Guérin–unresponsive non–muscle invasive bladder cancer.

Vicineum Granted Priority Review for High-Risk, BCG-Unresponsive Bladder Cancer

The FDA has granted priority review to sotorasib (formerly AMG 510) for the treatment of patients with 

 G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC), after at least 1 previous systemic therapy.

The decision was based on data from the phase 2 CodeBreaK 100 trial (NCT03600883), which showed that treatment with KRAS G12C inhibitor elicited a 6.8-month median progression-free survival (PFS) in patients with 

Moreover, at a median follow-up of 12.2 months, sotorasib induced an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%) and a disease control rate (DCR) of 80.6% (95% CI, 72.6%-87.2%). The median duration of response (DOR) was 10 months.

The FDA is slated to make a decision on the agent by August 16, 2021 per the Prescription Drug User Fee Act; this is 4 months earlier than the standard review cycle, according to Amgen, the drug developer.

“These results are encouraging and clinically meaningful for patients with advanced disease harboring the 

 G12C mutation,” Bob T. Li, MD, PhD, MPH, lead study author and medical oncologist a Memorial Sloan Kettering Cancer Center, said during a presentation of the data delivered at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer. “These are the patients who have progressive disease after standard treatment, so they need additional treatments, and the fact that we are seeing rapid tumor shrinkages and durable responses in these patients, is for me, a step forward and a win for patients.”

The phase 2 CodeBreaK 100 trial enrolled a total of 126 patients with locally advanced or metastatic NSCLC with a 

 G12C mutation assessed per central testing of tumor biopsies. Patients had to have progressed on previous standard therapies and they could not have active brain metastases.

In the trial, patients were given oral sotorasib at a dose of 960 mg until progressive disease. Radiographic scans were performed every 6 weeks up to week 48 and once every 12 weeks thereafter.

The primary end point of the trial was ORR per RECIST v1.1 criteria by blinded independent central review, while key secondary end points included DOR, DCR, time to recovery, PFS, overall survival, and safety. The examination of biomarkers served as an exploratory end point.

The median age of participants at baseline was 63.5 years and the majority, or 92.9% were either current or former smokers. Moreover, 69.8% of patients had an ECOG performance status of 1. Just under half, or 42.9%, of patients received 1 prior line of systemic treatment, while 34.9% received 2 lines, and 22.2% received 3 lines. About 90% of patients received previous platinum-based chemotherapy, 91.3% received PD-1/PD-L1 inhibitors, and 81.0% received both. Eighty-one percent of patients had progressed on previous platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

Additional results revealed that of those who achieved a response with sotorasib, 2.4% experienced a complete response, 34.7% had a partial response, and 43.5% had stable disease. Additionally, 16.1% experienced disease progression and 3.2% of patients were not evaluable or were missing a scan.

Moreover, responses achieved with the agent proved to be durable. The median time to objective response was 1.4 months. Seventy-two percent of responses were observed at the time of the first assessment. Just under half, or 43% (n = 20/46), of those who responded continued to receive treatment without experiencing progressive disease at the time of the data cutoff, which was December 1, 2020.

Tumor shrinkage of any magnitude was reported in 81% of patients (n = 101/124) and the median percentage of best tumor shrinkage among all patients who responded to treatment with sotorasib was 60%.

Results from the exploratory biomarker analyses showed that the clinical activity to sotorasib was observed across a range of biomarker subgroups, including those with PD-L1–negative or –low status, and also those with 

 mutations are generally linked with poorer outcomes in patients with NSCLC who previously received treatment with checkpoint inhibitors and chemotherapy.

Regarding safety, 69.8% of patients experienced any-grade treatment-related toxicities, while 19.8% experienced grade 3 effects. The majority of these effects were grade 1 or 2 in severity.

The most frequently reported treatment-related adverse effects (TRAEs) included diarrhea (31.0%, any grade; 4.0% grade 3), nausea (19.0%, any grade), alanine aminotransferase (15.1%, any grade; 6.3%, grade 3), aspartate aminotransferase (15.1%, any grade; 5.6%, grade 3), fatigue (11.1%, any grade), vomiting (7.9%, any grade), increased blood alkaline phosphatase (7.1%, any grade; 0.8%, grade 3), and maculopapular rash (5.6%, any grade).

TRAEs resulted in treatment discontinuation in 7.1% of patients, while 22.2% of patients experienced TRAEs that led to dose modification.

Previously, in December 2020, the FDA granted a breakthrough therapy designation for the drug for use as a potential treatment in patients with 

 G12C–mutated locally advanced or metastatic NSCLC, as determined via an FDA-approved test, after at least 1 prior systemic treatment.

FDA grants sotorasib priority review designation for the treatment of patients with 

 G12C-mutated locally advanced or metastatic non-small cell lung cancer. News release. Amgen. February 16, 2021. Accessed February 16, 2021. 

Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.


This article was originally published on OncLive as, "

FDA Grants Priority Review to Sotorasib for KRAS G12C–Mutated Advanced or Metastatic NSCLC.

The FDA has granted priority review to sotorasib for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer, after at least 1 previous systemic therapy.

Sotorasib Granted Priority Review for KRAS G12C–Mutated Advanced or Metastatic NSCLC

The FDA has approved trilaciclib (Cosela) to reduce the frequency of chemotherapy-induced bone marrow suppression in adults receiving certain types of chemotherapy for extensive-stage small cell lung cancer (ES-SCLC).1

“For patients with ES-SCLC, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, supervisory medical officer in the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “Today’s approval of [trilaciclib] will give patients a treatment option that can reduce the occurrence of a common, harmful side effect of chemotherapy.”

Trilaciclib was evaluated in 3 double-blind, placebo-controlled phase 2 trials in adult patients with ES-SCLC: G1T28-02 (NCT02499770), G1T28-05 (NCT03041311), and G1T28-03 (NCT02514447).2-4 In an analysis presented during the 

, investigators examined the pooled data from these trials to characterize the myelopreservation effects of the CDK4/6 inhibitor.

G1T28-02 evaluated the clinical benefit of trilaciclib in preserving the bone marrow and the immune system while augmenting the antitumor activity of chemotherapy when given before carboplatin and etoposide in the first-line treatment of patients with newly diagnosed disease. In this trial, patients were administered either trilaciclib or placebo on days 1 through 3 of each 21-day cycle.

In G1T28-05, investigators evaluated the potential benefit of the CDK4/6 inhibitor in preserving bone marrow and the immune system while encouraging antitumor efficacy when given with carboplatin, etoposide, and atezolizumab (Tecentriq) in the frontline treatment of patients with newly diagnosed disease. Here, patients received either trilaciclib or placebo on days 1 through 3 of each 21-day treatment cycle for up to 4 cycles as part of the induction phase; this was followed by atezolizumab, given every 21 days, as part of the maintenance phase.

In G1T28-03, investigators set out to understand the benefit of trilaciclib in preserving bone marrow and the immune system while boosting the antitumor activity of chemotherapy when administered prior to topotecan in patients with ES-SCLC who had received previous treatment. For this research, patients were given either trilaciclib or placebo on days 1 through 5 of each 21-day cycle of topotecan.

For the analysis, investigators examined trilaciclib with regard to myelopreservation and antitumor activity. The primary myelopreservation end points included duration of severe neutropenia (DSN), which was defined as grade 4 in cycle 1 and occurrence of severe neutropenia (SN) across the treatment period. Secondary myelopreservation end points were examined through hematopoietic lineage, including neutrophils, red blood cells, and platelets.

Additionally, to examine antitumor activity, investigators looked at objective response, progression-free survival (PFS), and overall survival (OS). Safety was also assessed in all study participants who received 1 or more doses of trilaciclib.

Data from a total of 119 patients who had received placebo prior to chemotherapy and 123 patients who received trilaciclib prior to chemotherapy were examined for the analysis. Baseline characteristics of patients proved to be comparable between the 2 groups of patients. Across the groups, most of the participants were Caucasian (97.6% and 92.4%, respectively), had an ECOG performance status of 0 or 1 (87.8% and 89.9%), and did not have brain metastases (77.2% and 75.6%).

Results demonstrated that tumor responses were comparable between the treatment groups; 49.1% of patients who received trilaciclib prior to chemotherapy experienced a response versus 51.8% of those who were given placebo (

 = .7879). PFS and OS also proved to be comparable between the groups. For those in the experimental arm, the PFS was 5.3 months (95% CI, 4.6-6.1) compared with 5.0 months for those in the placebo arm (HR, 0.80; 95% CI, 0.61-1.06; 

 = .1404). Additionally, the median OS was 10.6 months in both groups (HR, 1.00; 95% CI, 0.75-1.35; 

Trilaciclib, when given before chemotherapy, was found to lead to a significant decrease in most measures of multilineage chemotherapy-induced myelosuppression and the need for supportive care interventions. Moreover, the primary end points of DSN in cycle 1 and the occurrence of SN were found to be significantly decreased in those who received trilaciclib versus those given placebo; the mean DSN with trilaciclib and placebo was 0 compared with 4 days, respectively (

Of the patients who continued treatment after cycle 1, 8.9% of those in the trilaciclib group required 1 or more dose reductions of chemotherapy versus 30.3% of those in the placebo group (event rate per 100 cycles: 2.8 vs 9.3, respectively). Additionally, fewer patients who received trilaciclib reported serious toxicities compared with those who had received placebo, at 6.5% versus 10.1%, respectively; also, fewer patients needed treatment with intravenous antibiotics, at 19.5% versus 23.5%, respectively.

Regarding safety, treatment-emergent AEs (TEAEs) were experienced by 96.6% of those who received placebo compared with 94.3% of those who received trilaciclib. The most frequently experienced TEAEs comprised neutropenia, anemia, thrombocytopenia, nausea, and fatigue. Moreover, significantly fewer patients who received the CDK4/6 inhibitor prior to chemotherapy reported high-grade hematologic toxicities compared with those who were given placebo.

FDA approves drug to reduce bone marrow suppression caused by chemotherapy. FDA. News release. February 12, 2021. Accessed February 12, 2021. http://bit.ly/379OETw.

Weiss JM, Csoszi T, Maglakelidze M, et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase 1b/randomized phase II trial. 

. 2019;30 (suppl 5):1613-1621. doi:10.1093/annonc/mdz278

Daniel D, Kuchava V, Bondarenko I, et al. Trilaciclib decreases myelosuppression in extensive-stage small cell lung cancer (ES-SCLC) patients receiving first-line chemotherapy plus atezolizumab. 

. 2019;30(suppl 5):v713. doi:10.1093/annonc/mdz264.006

Hart LL, Andric ZG, Hussein MA, et al. Effect of trilaciclib, a CDK4/6 inhibitor, on myelosuppression in patients with previously treated extensive-stage small cell lung cancer receiving topotecan. 

. 2019;37(suppl 15):8505. doi:10.1200/JCO.2019.37.15_suppl.8505

This article was originally published on OncLive. 

The FDA has approved trilaciclib to reduce the frequency of chemotherapy-induced bone marrow suppression in adults receiving certain types of chemotherapy for extensive-stage small cell lung cancer.

FDA Approves Trilaciclib for Chemo-Induced Bone Marrow Suppression in Small Cell Lung Cancer

The FDA approved cemiplimab-rwlc (Libtayo) as the first immunotherapy for use in patients with advanced basal cell carcinoma (BCC) that has previously been treated with a hedgehog pathway inhibitor (HHI) or for whom a HHI is not appropriate.

The regulatory decision was based on data from an open-label, multicenter, non-randomized phase 2 trial, which included a total of 132 patients with unresectable locally advanced BCC or metastatic BCC, either nodal or distant.

A total of 112 patients were included in the efficacy analysis. Of these patients, 28 had metastatic BCC and 84 had locally advanced BCC. Participants in both cohorts had either progressed on HHI therapy, had not achieved an objective response following 9 months of HHI treatment, or were intolerant of previous HHI therapy.

Results from the trial showed that cemiplimab elicited a confirmed objective response rate of 21% (95% CI, 8%-41%) in patients with metastatic BCC and 29% (95% CI, 19%-40%) in those with locally advanced BCC.

“Patients with advanced forms of basal cell carcinoma face a very difficult prognosis,” Peter Adamson, global development head of Oncology and Pediatric Innovation at Sanofi, stated in the press release. “Thanks to the participation and support of researchers, clinicians, and patients around the world, we are proud to bring forward a new immunotherapy treatment option for appropriate patients in the United States affected by advanced BCC, another devastating non-melanoma skin cancer.”

The FDA approved cemiplimab-rwlc as the first immunotherapy for use in patients with advanced basal cell carcinoma that has previously been treated with a hedgehog pathway inhibitor (HHI) or for whom a HHI is not appropriate.

FDA Approves Cemiplimab for Advanced Basal Cell Carcinoma

The FDA has approved lisocabtagene maraleucel (Breyanzi) for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.

Each dose of the CAR T-cell product is developed using each patient's own T cells. The T cells are collected and genetically modified to comprise a new gene that facilitates targeting and elimination of lymphoma cells. Once the cells are modified, they are then infused back into the individual.

"Today's approval represents another milestone in the rapidly progressing field of gene therapy by providing an additional treatment option for adults with certain types of cancer affecting the blood, bone marrow, and lymph nodes," Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, stated in a press release. "Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens."

Data from the phase 1 TRANSCEND NHL 001 trial showed that liso-cel resulted in an objective response rate of 73% and a CR rate of 53%, with the time to first complete response (CR) or partial response occurring at a median of 1 month.

The median duration of response has not been reached at a median follow-up of 12 months. Some 60.4% and 54.7% of patients remained in response at 6 and 12 months, respectively, lead study author Jeremy Abramson, MD, said when presenting the data at the 2019 ASH Annual Meeting.

This article was originally published on OncLive.com as, "

FDA Approves Liso-Cel for Refractory Large B-Cell Lymphoma

Liso-Cel Approved for Refractory Large B-Cell Lymphoma

In response to the novel coronavirus disease 2019 (COVID-19) pandemic, investigators around the world channeled their efforts into acquiring a better understanding of the virus so that they could rapidly identify any weapons that may be used in the fight against its spread; this included turning to tried-and-true cancer drugs to see whether they could be repurposed to address this pressing need.

In an oral presentation delivered during the 2021 AACR Virtual Meeting on COVID-19 and Cancer, David C. Fajgenbaum, MD, MBA, MSc, the director of the Center for Cytokine Storm Treatment & Laboratory of the University of Pennsylvania, shared how his experience of having fallen critically ill with idiopathic multicentric Castleman disease, a rare and life-threatening disorder, led him down a career path that would explore new ways in which older drugs could be leveraged to save lives.

“When I became critically ill with idiopathic multicentric Castleman disease, I experienced multiorgan failure and became very, very sick,” Fajgenbaum shared. “I eventually began a race to try to find a drug that I could repurpose to save my life…Thankfully, I did fine one such drug by identifying the mTOR signaling pathway as a therapeutic target...This led me to my current career, which is leading a center that is focused on cytokine storm treatment…and dissecting these disorders to identify therapeutics that can be effective.”

In his talk, Fajgenbaum shared lessons from his work in Castleman disease and other cytokine disorders and the overlap with COVID-19, highlighted ongoing efforts to repurpose cancer drugs to combat the virus, and closed with future research directions.

Patients with idiopathic multicentric Castleman disease and those with COVID-19 can similarly experience cytokine storm in which they both experience multiorgan failure and require the assistance of a ventilator.

“But is cytokine storm really the right term for COVID-19? This is something that needs to be debated and it has been highlighted a number of times over the past year,” said Fajgenbaum. “[We] tried to define what cytokine storm is versus what it is not, because we need a definition to decide whether something fits within it.”

Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes that are typically defined by elevated levels of circulating cytokines and immune cell hyperactivation that can be triggered by several therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.

According to Fajgenbaum, cytokine storm can be defined as having the following:

If in the presence of a pathogen, this must be worse than or beyond what would be expected from controlling the pathogen normally. If no pathogen is present, there must be cytokine-driven organ dysfunction.

“When we think about this definition of cytokine storm in relation to COVID-19, clearly the most severe cases meet the first 2 components of the definition. The third one, organ dysfunction beyond the normal response, is a challenging one to delineate,” said Fajgenbaum. “What I like to do to really dig into this last one is [consider] response to therapies. If you target a specific cytokine or immunosuppress a population of patients and their outcomes improve, then we can use that to infer that their organ dysfunction is due to excessive inflammation as opposed to just purely a normal response to pathogens.”

Fajgenbaum added that research has shown that dexamethasone, a drug that has been in circulation since the 1960s and has been utilized to decrease inflammation in several conditions and cancers, resulted in improved outcomes in patients with severe COVID-19 infection.3 Because of this, Fajgenbaum believes that patients with severe infection should fall within this definition of cytokine storm, whereas mild and moderate cases potentially would not.

Several approaches are used to identify a drug that is being used in one condition to see whether it can be repurposed for use in another area, according to Fajgenbaum.

For example, high throughput drug screens can be used to test several compounds on a cell line. Artificial intelligence can be used to examine published databases to determine connections that may not be readily apparent. Translational research can also be conducted to identify potential targets. Once identified, databases can be used to determine which available drugs are able to bind to those targets. Then, the drug can be moved into mechanistic studies for further exploration.