Denise Myshko

Findings from a A phase 3 trial (NCT02632409) evaluating adjuvant nivolumab (Opdivo) following surgery versus placebo demonstrated an improvement in median disease-free survival (DFS) in patients with muscle-invasive urothelial cancer (MIUC), according to results from the CheckMate 274 trial presented at the 2021 Genitourinary Cancers Symposium. 

Investigators found that nivolumab conferred a median DFS benefit in both the intention-to-treat (ITT) and PD-L1–positive populations. In the ITT population, DFS in those treated with nivolumab (n = 353) was 21.0 months, compared with 10.9 months with placebo (n = 356; HR, 0.70; 98.31% CI, 0.54-0.89; 

“This corresponds to a 30% reduction in the risk of disease recurrence or death with nivolumab,” said lead author Dean Bajorin, MD, the Frederick R. Adler senior faculty chair at Memorial Sloan Kettering Cancer Center in New York. “The median DFS is nearly double with nivolumab compared to placebo.”

In the PD-L1–positive population, the median DFS in those treated with nivolumab (n = 140)  was not reached, compared with 10.8 months in the placebo arm (n = 142; HR, 0.53; 98.87% CI, 0.34-0.84; 

 < .001). “This corresponds to a 47% reduction in the risk of disease recurrence or death with nivolumab,” Bajorin said.

A subgroup analysis of the ITT population found no differences related to age, sex, region, or performance status, he added.

The monoclonal antibody also improved median non–urothelial tract recurrence-free survival (NUTRFS), a secondary end point of the study, as well as distant metastasis free survival (DMFS), an exploratory end point, in both the ITT and the PD-L1–positive patient populations

In the ITT population, those treated with nivolumab experienced NUTRFS of 24.6 months versus 13.7 months in the placebo group (HR, 0.72; 95% CI, 0.58-0.89). In the PD-L1– positive population, NUTRFS in those treated with nivolumab was not reached versus 10.9 months in the placebo group (HR, 0.54; 95% CI, 0.38-0.77).

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with muscle-invasive urothelial carcinoma,” Bajorin said. “These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy.”

The randomized, double-blind CheckMate 274 study evaluated the efficacy and safety of adjuvant nivolumab versus placebo in patients with high-risk MIUC after radical surgery. Patients were randomized 1:1 to receive nivolumab 240 mg administered once every 2 weeks or placebo for up to 1 year of adjuvant treatment.

Eligible patients had radical surgery within 120 days with or without neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemotherapy and were disease-free as evidenced by imaging.

The primary end point of the study, according to investigators, was DFS in the ITT population and in patients with tumor PD-L1 expression of at least 1%. The median follow-up was 20.9 months for nivolumab and 19.5 months for placebo.

In total, 353 patients were randomized to receive nivolumab and 356 patients received placebo. In the nivolumab arm, 53.3% of patients discontinued treatment and in the placebo arm, 56.3% of patients discontinued. This was most commonly due to disease recurrence.

Among patients in the nivolumab arm, the tumor of origin was urinary bladder carcinoma in 79% of patients and upper tract disease in 21% of patients. In the placebo arm, the tumor of origin was the bladder in 78.9% of patients and upper tract disease in 21.1% of patients. About 40% patients in both arms were PD-L1 positive and about 43% had received prior cisplatin based neoadjuvant chemotherapy.

The safety of nivolumab was consistent with previously reported studies in patients with solid tumors. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 17.9% of patients in the nivolumab arm and 7.2% of patients in the placebo arm.

Any-grade TRAEs leading to discontinuation occurred in 12.8% in the nivolumab arm and 2% of patients in the placebo arm. The most common TRAEs in the nivolumab arm were pruritis, fatigue, diarrhea, and rash.

Nivolumab is approved by the FDA as a monotherapy for the treatment of platinum-resistant urothelial carcinoma.

Bajorin DF, Witjes JA, Gschwend J, Schenker M. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). 

Articles

Findings from a A phase 3 trial evaluating adjuvant nivolumab following surgery versus placebo demonstrated an improvement in median disease-free survival in patients with muscle-invasive urothelial cancer, according to results from the CheckMate 274 trial presented at the 2021 Genitourinary Cancers Symposium. 





Adjuvant Nivolumab Confers 30% Reduction in Disease Recurrence in MIUC

After treatment with savolitinib, undetectability of 

ex14) in the circulating tumor DNA (ctDNA) of patients with non‒small cell lung cancer (NSCLC) was found to be associated with prolonged progression-free survival (PFS), and overall survival (OS), according to a poster presented during the virtual AACR Annual Meeting 2021.

ex14 clearance upon savolitinib treatment was correlated with significantly longer PFS and OS compared with those who had detectable 

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

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

The median PFS for patients treated with savolitinib who had undetectable 

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

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

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

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

For patients treated with savolitinib who were non-evaluable for 

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

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

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

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

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

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

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

Sixty-six patients provided baseline plasma samples, of which 

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

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

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

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

ex14+; 70 of these patients were treated.

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

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

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

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

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

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

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

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

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

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

After treatment with savolitinib, undetectability of MET Exon 14 in the circulating tumor DNA of patients with non‒small cell lung cancer was found to be associated with prolonged progression-free survival, and overall survival.

Undetectable METex14 After Savolitinib Correlates With Positive Outcomes in NSCLC

In the phase 3 VISION study, treatment with the MET inhibitor, tepotinib showed durable clinical activity as treatment of patients with 

ex14) non‒small cell lung cancer (NSCLC), according to updated results presented during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer.

Paul K. Paik, MD, clinical director, Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, presented results from subgroup analyses of treatment-naïve and previously-treated patients from the VISION study (NCT02864992). VISION is a single arm, phase 2 study. As of data cut-off of July 1, 2020, 152 patients had ≥9 months of follow-up and were assessed for efficacy (Cohort A); 255 patients were evaluated for safety (Cohort A and Cohort C).

ex14 skipping NSCLC received oral tepotinib 500 mg once daily. Efficacy outcomes were consistent in patients who received prior platinum-based chemotherapy and/or immune-oncology (IO), study authors found.

In treatment-naïve patients from Cohort A (n = 69), the overall objective response rate (ORR) was 44.9% (95% CI, 32.9 to 57.4), with a median duration of response (DOR) of 10.8 months (95% CI, 6.9-not evaluable). Progression free survival (PFS) was 8.5 months (95% CI, 6.8-11.3).

In previously-treated patients from Cohort A (n = 83), overall ORR was 44.6% (95% CI, 33.7- 55.9), median DOR was 11.1 months (95% CI, 9.5-18.5), and median PFS was 10.9 months (95 CI, 8.2-12.7).

Tepotinib was generally well tolerated across therapy lines, with mostly mild moderate adverse events (AEs) and few discontinuations. The most common treatment related AE, peripheral edema, was mostly low grade (Grade ≥3: 7%) and rarely led to discontinuation (4%). Other common AEs include nausea, diarrhea, blood creatine increase, and hypoalbuminemia. The safety profile was consistent in patients who received prior IO, study authors found.

In the efficacy population, patients had a median age of 73.4 years (range 41-94), 76 were male (52.1%), 76 had a smoking history (52.1%), and 81 had received prior treatment for advanced/metastatic disease (55.5%). Seventy-two patients had received prior platinum-based chemotherapy for metastatic disease, either alone (n=63) or in combination with immunotherapy (n=9).

The FDA granted priority review for tepotinib under the FDA Real-time Oncology Review pilot program in August 2020 for the treatment of adult patients with NSCLC whose tumors have a mutation that leads to mesenchymal-epithelial transition exon 14 (

The application was based on early analysis of the VISION study, which was published in 

 and presented during the American Society of Clinical Oncology Virtual Scientific Program.

 In this review, at data cut off of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% CI, 36-57), with a median DOR of 11.1 months (95% CI, 7.2-not estimated). The response rate was 48% (95% CI, 36-61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37-63) among 60 patients in the tissue-biopsy group.

In this earlier analysis, adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients.

Tepotinib was granted breakthrough therapy designation by the FDA in September 2019 for the treatment of patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy.

In March 2020, the Japanese Ministry of Health, Labour and Welfare approved tepotinib for the treatment of patients with unresectable, advanced or recurrent NSCLC with 

ex14 skipping alterations. The agent is not available outside of Japan.

1. Paik PK, Sakai H, Felip E, et al. Tepotinib in patients with 

ex14) skipping advanced NSCLC: updated efficacy from VISION Cohort A. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract MA11.05

2. FDA accepts filing of new drug application for tepotinib for the treatment of patients with metastatic NSCLC with 

ex14 skipping alterations. News release. Merck KGaA. August 25, 2020. Accessed January 31, 2021. http://bit.ly/3cmp6pI

3. Paik PK, Felip E, Veillon R, et Tepotinib in non‒small cell lung cancer with 

. September 3, 2020. doi:10.1056/NEJMoa2004407

4. Merck KGaA, Darmstadt Germany, announces FDA breakthrough therapy designation for investigational therapy tepotinib in patients with metastatic NSCLC with MET ex14 skipping alterations. News release. Merck KGaA. September 11, 2019. Accessed January 31, 2021. http://bit.ly/2YxxbQk

In the phase 3 VISION study, treatment with the MET inhibitor, tepotinib showed durable clinical activity as treatment of patients with MET exon 14 skipping non‒small cell lung cancer.

Tepotinib Induces Durable Responses in MET exon 14 Skipping NSCLC

Adjuvant treatment with pertuzumab (Perjeta) demonstrated a trend for greater benefit in patients with early breast cancer with a HER2 single-activated pathway determined by molecular subtyping using BluePrint assay, according to an exploratory analysis of the APHINITY study presented during the 2020 San Antonio Breast Cancer Symposium.

Investigators also found, in this trial in which all cancers were pathologically confirmed to be 

 positive, BluePrint’s single activated basal subtype showed a significantly worse prognosis than other single activated subtypes.

“Based on predictive analysis, there was a trend of greater benefit with the addition of pertuzumab to trastuzumab (Herceptin) in patients with BluePrint 

 single-activated tumors compared with other groups,” Ian E. Krop, MD, PhD, said during the poster presentation. Krop is associate chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, and clinical research director of the Breast Oncology Center at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

BluePrint, an 80-gene molecular subtyping test, classifies early breast cancer into RNA-based functional molecular subtypes—basal, luminal, and 

 The test evaluates the functionality of receptor cell signaling and complements immunohistochemistry and fluorescence in situ hybridization, providing information regarding patient chemotherapy or hormonotherapy resistance for more informed treatment decision-making.

Study investigators hypothesized that BluePrint could identify a subgroup of patients who would derived further benefit from the addition of pertuzumab to chemotherapy/trastuzumab from the population of those evaluated in the phase 3 APHINITY trial (NCT01358877). Pertuzumab is approved to treat patients with early breast cancer in combination with chemotherapy and trastuzumab.

In total 4805 patients with histologically confirmed 

-positive early breast cancer were treated with standard adjuvant chemotherapy and trastuzumab plus either pertuzumab or placebo for 1 year. With a median follow up of 45 months, the primary analysis showed significant invasive disease-free survival (iDFS) benefit for the addition of pertuzumab to chemotherapy and trastuzumab at 3 years with a hazard ratio of 0.81 (95% CI, 0.66-1.00; 

BluePrint analysis was performed using RNA sequencing data from a subset of APHINITY samples (N = 969) with usable BluePrint subtyping. Investigators found that 50% of the cancers were classified as luminal subtype (N = 485), 28% of HER2 subtype (N = 275), and 22% as basal (N = 210). Patients’ tumors were further classified as single-activated or dual-activated. Single activated subtype was seen in 123 patients of 210 patients (59%) in the basal subtype, 413 patients of 485 patients (85%) luminal subtype, and 139 patients of 275 patients (51%) of HER2 subtype cancers.

A majority of patients in all BluePrint groups were lymph-node positive, over 35 years old, and received an anthracycline containing regimen. Most patients in the luminal group were HR positive whereas a majority of BP basal and BP HER2patients were HR negative.

A greater benefit with the addition of pertuzumab to chemotherapy/trastuzumab was suggested in the single activated 

 subtype compared with other groups—single HER2 HR was 0.56 (95% CI, 0.27-1.15), single basal HR was 0.89 (95% CI, 0.44-1.79) and single luminal HR was 0.93 (95% CI, 0.61-1.41).

“While most cancers have 1 activated functional BluePrint pathway, some cancers may display 2 functionally activated BluePrint pathways, Krop said.

Research is ongoing to confirm these findings and to further define the role of BluePrint in the characterization of 

1. Krop IE, Mittempergher L, Paulson JN, Andre F, et al. Prediction of benefit from adjuvant pertuzumab by BluePrint RNA sequencing in the APHINITY trial. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 9, 2020. Abstract PD3-01. Accessed December 10 2020. 

2. Agendia BluePrint. Agendia Precision Oncology. Accessed December 10, 2020. https://bit.ly/39Y7Fuk

3. Perjeta. Prescribing information. Genentech; 2020. Accessed December 10, 2020. 

Adjuvant treatment with pertuzumab demonstrated a trend for greater benefit in patients with early breast cancer with a HER2 single-activated pathway determined by molecular subtyping using BluePrint assay.

Denise Myshko | Authors

Articles

Adjuvant Nivolumab Confers 30% Reduction in Disease Recurrence in MIUC

Undetectable METex14 After Savolitinib Correlates With Positive Outcomes in NSCLC

Tepotinib Induces Durable Responses in MET exon 14 Skipping NSCLC

BluePrint Subtyping May Predict Benefit of Adjuvant Pertuzumab in Early Breast Cancer