Conor Killmurray

Researchers saw encouraging signs of efficacy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) with mutant 

 variant alle frequency (VAF) treated on tipifarnib on a phase 2 clinical trial, according to results published in the 

Among the 30 patients in the single-arm, open label phase 2 KO-TIP-001 study (NCT02383927) enrollment on tipifarnib was further limited to patients with a mutant 

 VAF greater than 20%, which was defined as high VAF, after an ad hoc analysis showed efficacy in these patients may be enriched. Twenty-two of the patients had high VAF, but 20 were evaluable for response at the time of data cutoff and researchers recorded an objective response rate (ORR) of 55% (95% CI, 31.5-76.9), meeting the primary end point of the study. The ORR in the intent to treat population (n = 22) was 50% (95% CI, 30.7-69.3).

Twelve patients with high VAF had a VAF greater than 35% (37%-90%) and had an ORR of 58.3%, compared to patients with high VAF less than 35% (23%-33%) who had a 50% ORR. Moreover, 3 patients of the 12 with VAF greater than 35% had an albumin of < 3.5 g/dL with 1 (33.3%) achieving a response. These responses were achieved rapidly, as 8 of 11 patient met the criteria of the first tumor assessment within 8 weeks. Nine patients did not receive a response, however, but all were considered to have stable disease (SD), while 6 patients saw a minor tumor regression.

For this study, patients were initially given tipifarnib at 900 mg orally twice a day on days 1-7 and 15-21 of 28-day cycles. Nine patients required dose reduction to manage toxicities initially, and the treatment was amended to 600 mg twice a day daily in the same cycles moving forward. Tumors were assessed every 8 weeks in the first 6 months and then every 12 weeks until disease progression.

Progression-free survival (PFS) was also found to be statistically significant at a median of 5.6 months (95% CI, 3.6-16.4, 

 = .0012) on tipifarnib compared to a median PFS of 3.6 months (95% CI, 1.3-5.2) for patients on their last prior therapy. Patients on tipifarnib who experienced a partial response to treatment had a PFS of 9.5 months (95% CI, 5.5-NA) compared to a PFS of 4 months (95% CI, 1.9-NA) in patients with SD. Researchers also observed a significant median overall survival (OS) of 15.4 months (95% CI, 7.0-29.7) for patients on tipifarnib.

“The median OS of 15.4 months with tipifarnib is also longer than historically reported for treatments used in a similar setting (5.1-8.4 months),” researchers wrote. “Another striking observation was the clinical benefit rate for the high–mutant 

 VAF efficacy evaluable patients were 100% (11 of 20 with PR and 9 of 20 with SD), providing additional evidence for the role of mutant 

 as an oncogenic driver in these tumors and the ability of (farnesyltransferase inhibitors) to therapeutically target it.”

Secondary endpoints of the study include safety and tolerability, and tipifarnib was considered safe and tolerable in this study. Safety was evaluated in all 30 patients of the trial and the most common treatment-emergent adverse events (TEAEs) in any grade, regardless of their VAF status, were anemia, neutropenia, leukopenia, lymphopenia, and nausea. Three patients had to discontinue treatment due to TEAEs, which included 2 patients who had laryngeal obstruction and 1 patient with respiratory failure. However, the researchers determined these were not related to tipifarnib but the disease itself. At the time of data cutoff, no patient with high VAF discontinued tipifarnib due to adverse events.

The farnesyltransferase inhibitor was previously a part of phase 2 and 3 clinical trials that looked at the targeted therapies use in patients with tumor types that were predilected to have high levels of 

 mutations but results from these trials were not significant. However, for patients with HNSCC, derived xenograft models showed the inhibitor reduced tumor size in 

 is a driver oncogenic mutation that occurs in 4-8% of patients with HNSCC, which led to researchers wanting to observe an expanded use of the inhibitor in the patient population, as they do not have many other options/

“A review of publicly available HNSCC genomic data from The Cancer Genome Atlas reveals that the VAF threshold of at least 20% would exclude more than one fourth of 

 mutant tumors and a threshold of at least 35% would apply to < 3% of patients with HNSCC overall,” wrote Alexander T. Pearson, MD, PhD, and Everett E. Vokes, MD, in an editorial in 

 accompanying the study. “The VAF-clinical response correlation is imperfect, with responses observed across the spectrum of 

 VAFs. Significant enrichment occurs at higher thresholds, but further study should be dedicated to optimize the clinical utility of VAF as a biomarker.”

Ho AL, Brana I, Haddad R, et al. Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations. 

. 2021 Mar 22:JCO2002903. doi: 10.1200/JCO.20.02903

Pearson AT, Vokes EE. Is This the Dawn of Precision Oncology in Head and Neck Cancer? 

. 2021 Apr 20:JCO2100569. doi: 10.1200/JCO.21.00569

Articles

Results from the phase 2 study of farnesyltransferase inhibitor tipifarnib showed significant responses in patients with recurrent and/or metastatic head and neck squamous cell carcinoma and demonstrated that variant alle frequency could be a potential biomarker in this patient population.

Tipifarnib Elicits Encouraging Responses in Patients With Recurrent or Metastatic HNSCC

Preclinical research suggests that enhancer zeste homologs 1 and 2 (EZH1/2) could be a potential novel target for the treatment of patients with aggressive ibrutinib‐resistant 

 via CDKN1C‐mediated cell cycle arrest, according to a report published in 

 MCL patient-derived xenograft mouse model, researchers found that oral administration of the EZH1/2 inhibitor OR-S1 inhibited MCL tumor growth significantly, whereas ibrutinib did not. OR-S1 also modulated B-cell activation, differentiation, and cell cycle after looking at comprehensive gene cell expression. Analysis of 

 growth showed that OR-S1 was also more effective than the EZH2 inhibitor GSK126.

“We identified CDKN1C (p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation,” researchers wrote in their preclinical report. The dual inhibition of EZH1/2 has proven to be a target that researchers can continue to investigate for not just patients with MCL, but other hematologic malignancies as well.

OR-S1 is considered a close analog treatment to the EZH1/2 inhibitor valemetostat (DS-3201) that had previously shown anti-tumor benefit in multiple hematological malignancies in preclinical studies.2 In a phase 1 study [NCT02732275] of valemetostat, researchers looked at 38 patients with relapsed or refractory non-Hodgkin lymphoma (NHL), which MCL is a rare subtype of. They found that among patients there was an objective response rate of 47.2% and 15 patients were able to stay on the treatment for more than 24 weeks with tumor shrinkage. This demonstrated to researchers that EZH1/2 was a viable target to continue studying in patients with NHL.

EZH1/2 are subunits of polycomb repressive complexes (PRC) of polycomb group proteins that regulate the expression of target genes. PRC are recurrently mutated or highly expressed in hematologic malignances, in particular, EZH2 is both an oncogene and tumor suppressor gene, according to Issay Kitabayashi, MD.3

High expression of EZH2 is associated with tumor aggressiveness in hematologic malignancies like MCL and can accelerate tumor growth. In a review article Kitabayashi, chief of the division of hematological malignancy, at the National Cancer Center Research Institute, Tokyo, Japan, discussed the role of OR-S1 in disrupting PRC during the growth of the tumor. Moreover, OR-S1 suppresses H3K27me3, the epigenetic modification of Histone H3, which plays a role in hematologic malignance’s growth and spread.

Kagiyama Y, Fujita S, Shima Y, et al. CDKN1C-mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib. 

. Published online March 31, 2021. doi: 10.1111/cas.14905.

Morishima S, Ishitsuka K, Izutsu K, et al. First-in-Human Study of the EZH1/2 Dual Inhibitor Valemetostat in Relapsed or Refractory Non-Hodgkin Lymphoma (NHL) - Updated Results Focusing on Adult T-Cell Leukemia-Lymphoma (ATL). 

. 2019; 134 (suppl 1): 4025. doi: 10.1182

Kitabayashi, I, Nakagawa M. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. 

. 1028;109(8): 2342–2348. doi: 10.1111/cas.13655

A new report on ibrutinib-resistant mantle cell lymphoma patient-derived xenograft mouse models shows the potential benefit of the EZH1/2 inhibitor OR-S1, as other similar inhibitors have shown benefit in patients with hematologic cancers.  

Preclinical Research Shows Potential for EZH1/2 Dual Inhibitor In Relapsed/Refractory MCL

For patients non–small cell lung cancer (NSCLC) who previously progressed on chemotherapy and immune checkpoint inhibitors, ceralasertib plus durvalumab (Imfinzi) proved effective compared with patients with the same profile who received durvalumab alone, according to findings from the ongoing HUDSON study.

The study’s primary end point was objective response rate (ORR), but preliminary data from the HUDSON (NCT03334617) trial, presented at the 2020 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC), also showed superior efficacy in the progression-free survival (PFS) and overall survival (OS) rates of patients on ceralasertib. Results show that the ATR kinase inhibitor is beneficial for high-risk patients with NSCLC who have limited treatment options after progressing on previous treatments.

“The prognostic profiles of patients enrolled based on predefined biomarker selection criteria can differ [from] those without predefined biomarker criteria. Patients with acquired resistance appear to have a higher life expectancy compared with those who relapse earlier,” explained Benjamin Besse, MD, lead author and member of the HUDSON study group, in an interview with 

HUDSON is an open-label, biomarker-directed, multiarm, multicenter, phase 2 umbrella study evaluating 261 patients with NSCLC, as of this writing. Patients on the trial had to have previously received platinum doublet chemotherapy and experienced immune checkpoint inhibitor failure. All patients received durvalumab. Other therapies combined with durvalumab included ceralasertib, olaparib (Lynparza), and oleclumab (MEDI9447). Investigators used preexisting local next-generation sequencing data to enable rapid patient allocation to biomarker-matched groups.

Overall, the HUDSON trial is evaluating the drivers of immune checkpoint blockade resistance and methods to overcome this resistance, to increase patient benefit from immune therapy. Investigators focused not only on patient biomarkers but also the resistance that patients had shown to previous treatment. According to Besse, head of the department of medical oncology at the Institut Gustave Roussy in Villejuif, France, the study design was focused on 2 patient populations with NSCLC, those with predefined biomarkers and those without.

In the preliminary data, those 2 populations were stratified into group A (n = 85), those with a matched biomarker profile, or group B, those with nonmatched profiles.

Group B was further divided into patients with acquired resistance (ACQ), defined as disease progression after more than 24 weeks of prior immunotherapy (

), and primary resistance (PRI), defined as disease progression at 24 weeks from the onset of prior immunotherapy. Ninety-four evaluated patients were in the ACQ cohort, and 74 patients were in the PRI cohort, respectively.

Patient age ranged from 33 to 65 years. In the biomarker-matched ceralasertib arm, 94.4% of patients had a previous history of smoking. Also, in the biomarker-matched ceralasertib arm, 44.4% of patients had 3 or more lesions, whereas 39% and 41.7% of patients exhibited 3 or more lesions in the PRI and ACQ arms, respectively.

Biomarkers that patients were matched with included patients with homologous recombination repair gene mutation (HRRm), 

mutations in their tumor, CD73 molecule, 

mutant). Patients with HRRm (n = 21) and 

(n = 21) mutations in their tumor were given olaparib (Lynparza) in combination with durvalumab, and patients with CD73 (n = 23) in their tumor were given oleclumab. 

m groups received fam-trastuzumab deruxtecan (Enhertu). The only biomarker patient group who received ceralasertib was those with 

mutation in their tumor (n = 18). Enrollment for the 

groups is ongoing, and no results were available. However, median ORR was highest in the group with 

, at 13.3%, with a median PFS of 7.43 months (80% CI, 3.45-9.46); 100% of patients were followed through after 6 months.

ORR was not reached in the CD73 group but was reached in the HRRm group, at 4.8%, with the 

group reflecting the same ORR; however, the median PFS was greater in the HRRm group, at 2.79 months (80% CI, 1.48-5.26) compared with 1.41 months in the 

group (80% CI, 1.38-1.81). In group B, both patients with PRI and ACQ demonstrated higher ORR rates at 11.1% and 8.7%, respectively. The median PFS was also highest in these groups, at 4.24 months (80% CI, 1.94-6.77) in the PRI group and 4.96 months (80% CI, 3.55-5.98) in the ACQ group. The only other set of patients in group B to achieve an ORR was the olaparib arm of the PRI group, at 4.3% with a median PFS of 3.38 months (80% CI, 2.10-4.93).

“When the results of those different subcohorts are placed next to each other, as was done at the WCLC presentation, one can see how similar or different the numerical results are, as if one was comparing a series of single-arm trials,” explained Besse. “The responses from the ceralasertib cohorts indicate a more favorable efficacy than was seen in the other treatment combinations with similar maturity of data. It is, however, hard to conclude anything beyond this.”

The treatment schedule for ceralasertib consisted of a 7-day cycle followed by two 28-day cycles with dosing occurring on each day of the first cycle and days 22 to 28 of the 28-day cycles. Durvalumab was given on day 1 of the 28-day cycles. An exploratory analysis, also presented at WCLC by Besse, found that the combination treatment has a role in immune activation via ceralasertib.

 However, this was translational data from 8 patients in the 

biomarker subcohort and 17 patients from the biomarker-negative group, and clinical data have yet to be presented.

The analysis found 4 different gene signatures for macrophages1-3 that decreased with ceralasertib. There was also a 2-fold reduction in peripheral IL-8 gene expression in paired blood samples among 19 patients considered to have controlled disease, defined by partial response or stable disease by RECIST v1.1 criteria, compared with the 6 patients showing progressive disease. During the ceralasertib-only period of treatment, the investigators found modified biomarkers displaying peripheral immunity with significant increases in antigen presentation, gene signature, and decreases in T-cell and natural killer cell signatures. Moreover, these changes in gene expressions were associated with the treatment, leading investigators to confirm whether these characteristics are to be considered prognostic or predictive of response.

HUDSON’s Impact on the Community Setting

Looking at the challenges ahead, Besse pointed out that community oncologists will need to make their own risk-benefit analysis for patients. The trial is ongoing, and safety is continually being monitored. However, he believes that the benefits outweigh the current adverse effects, making it a favorable choice for oncologists.

In particular, he highlighted the ability of community oncology practices to bring this clinical trial to patients who may not otherwise get it without access to hospitals in the academic setting, especially as phase 3 preparations ramp up.

1. Besse B. HUDSON: An open-label, multi-drug, biomarker-directed, phase 2 platform study in patients with NSCLC who progressed on anti-PD(L)1 therapy. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract OA07.08. https://bit.ly/3lJ6bYC

2. Lao-Sirieix S, Heymach J, Forde P, et al. P2.01-07 Open-label, biomarker-directed platform study in NSCLC patients who progressed on an anti-PD-(L)1-containing therapy (HUDSON). 

. 2019;14-10. doi: https://doi.org/10.1016/j.jtho.2019.08.1351

3. Besse B. Immuno-Modulatory Effects of Ceralasertib in Combination withdurvalumab in NSCLC with progression on anti-pd(l)1 treatment (HUDSON). Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract p16.07. https://bit.ly/3lJ6bYC

For patients non–small cell lung cancer who previously progressed on chemotherapy and immune checkpoint inhibitors, ceralasertib plus durvalumab proved effective compared with patients with the same profile who received durvalumab alone, according to findings from the ongoing HUDSON study.



Ceralasertib/Durvalumab Combination Stands Out in HUDSON Trial for Patients With NSCLC

D-0316 showed clinically meaningful efficacy in patients with 

-positive non–small cell lung cancer (NSCLC) who progressed on prior treatment according to an analysis of phase 2 study results presented at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.1

 tyrosine kinase inhibitor [TKI] D-0316 is selective for EGFR-TKI and T790M resistance mutations in patients with NSCLC, which most patients will develop a resistance too after frontline treatment with first- and second-generation EGFR-TKIs. The single-arm phase 2 study (NCT03861156) of D-0316 looked at 290 patients who previously progressed on first line EGFR-TKI treatment and had 

Patients from China first enrolled on the study (n = 176) were given 50 mg of D-0316, which saw an objective response rate (ORR) of 51.1% (95 CI, 43.3-58.7) when first assessed in 2019, but the dosage was altered to 75-100 mg after a 21-day lead in on treatment. The ORR of the 290 patients that fulfilled enrollment was 64.8% (95% CI, 59-70.3) and a disease control rate (DCR) of 95.2% (95% CI, 92-97.3), which met the primary endpoints of the study. Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were premature at the time of the conference.

D-0316 also had a favorable response in subgroups of the study, according to researchers, who looked at 105 patients with central nervous system (CNS) metastases. The ORR among this group was 52.9% (95% CI, 35.1-70.2) for patients that had the higher dose in comparison to an ORR of 20% (95% CI, 4.3-48.1) for patients who had 50 mg of D-0316. PFS was also not reached in this group. Among 34 patients who had brain metastases at the baseline of the study 18 of these patients achieved a partial response on the therapy. After a median follow-up of 5.5 months, investigators also saw that 188 patients had a confirmed partial response by an independent review committee.

“The median duration of exposure in the 75-100mg cohort was 20.6 weeks,” explained Shun Lu, MD, lead investigator from the Shanghai Chest Hospital, in a virtual presentation at the virtual AACR Meeting 2021.“The investigator-assessed median PFS was 9.7 months and the median (iPFS) was 10.3 months.” In comparison to the 50 mg cohort, Lu added, the median PFS was 8.4 months and median iPFS was 8.6 months.

The median age of patients in the 75-100 mg cohort was 62.5 years old and 65.5% of patients were female.1 Patients with an ECOG performance status of 1 or 2 were accepted on the trial, with a majority of patients (78.6%) having a performance status of 1. Overall, 154 patients with stage 4a NSCLC and 299 patients with stage 4b NSCLC were observed on the study between both cohorts. The most common 

 (67%) followed by patients whose tumor had 21-

Treatment-related adverse effects (TRAEs) were observed on the study, but the most common were grades 1 and 2. The most common of these TRAEs included thrombocytopenia (57.2%), headache (27.6%), leukopenia (23.4%), anemia (22.1%), and rash (20.7%). The most common TRAE at grade 3 or higher was also thrombocytopenia (11.7%), other grade 3 TRAEs included pulmonary embolism (4.1%), electrolyte imbalance (2.1%), leukopenia (1.9%), and rash (1.3%). One death was due to TRAE (interstitial lung disease) and 6 patients were observed with interstitial lung diseases (2.1%).

“The investigator ORR of 52.9%, suggested that D-0316 showed clinical meaningful efficacy against CNS metastases and the study demonstrated potentially improved efficacy, with manageable toxicities, of D-0316 therapy,” Lu concluded.

Shun L, Zhang Y, Zhang G, et al. D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study. Abstract presented at: American Association for Cancer Research Virtual Annual Meeting 2021; April 10-12, 2021; Virtual. Abstract CT170

More than half of patients with T790M-positive non-small cell lung cancer had a response to the  third generation EGFR TKI D-0316 in a phase 2 study.

Conor Killmurray | Authors

Articles

Tipifarnib Elicits Encouraging Responses in Patients With Recurrent or Metastatic HNSCC

Preclinical Research Shows Potential for EZH1/2 Dual Inhibitor In Relapsed/Refractory MCL

Ceralasertib/Durvalumab Combination Stands Out in HUDSON Trial for Patients With NSCLC

D-0316 Shows Clinically Meaningful Improvement in Patients with T790M+ and EGFR+ NSCLC