Colleen Moretti 

Consistent efficacy was seen with selpercatinib (Retevmo) in patients with 

 fusion-positive non-small cell lung cancer (NSCLC), regardless of prior treatments, according to findings from the LIBRETTO-001 trial (NCT03157128) presented at the virtual 2021 ASCO Annual Meeting.

“(The) results, (however), should be interpreted with caution, as a limitation of this analysis was that immediate prior response assessment was based on physician-reported best response in patients’ medical history and may not follow RECIST criteria,” the study authors wrote in the poster. 

The study was conducted across 89 sites in 16 countries and consisted of 218 evaluable patients (median age, 61 years) who previously received platinum-based chemotherapy. Most patients had an ECOG score of 0/1 (37%/61%) and received a median of 2 (range, 1-15) prior systematic therapies. The study’s primary endpoint was objective response rate (ORR), with additional endpoints of progression-free survival (PFS), duration of response (DOR) and safety.

The study compared physician reported best overall response (BOR) from last systematic therapy received prior to enrollment with selpercatinib BOR by independent review committee, and each patient served as their own control.

The ORR with selpercatinib was 57% which was “markedly higher,” the authors wrote, than responses with prior treatment which was 16%.

A total of 108 patients (50%) did not respond to prior therapy but responded to treatment with selpercatinib. There were 16 patients (7%) who responded to both selpercatinib and prior therapy, 18 patients (8%) who responded to prior therapy but not selpercatinib and 76 patients (35%) who did not respond to either.

ORR was improved regardless of prior therapy, chemotherapy plus immune checkpoint inhibitor (ICI) (57% versus 14%), single-agent ICI (48% versus 3%) or chemotherapy (58% versus 15%).

Fewer patients had progressive disease with selprecatinib BOR (2%), compared with immediate prior therapy (28%). Median DOR was also notably longer compared with prior therapy, 11.8 months versus 3.4 months.

The authors concluded noting that the global, randomized phase 3 LIBRETTO-431 trial (NCT04194944) evaluating selpercatinib compared with standard frontline therapy (pemetrexed/carboplatin with or without pembrolizumab [Keytruda]) is ongoing.

Drilon A, Gautschi O, Besse B, et al. Response to selpercatinib versus prior systematic therapy in patients (pts) with 

 fusion + non-small cell lung cancer (NSCLC). 

Articles

Consistent efficacy was seen with selpercatinib in patients with RET fusion-positive non-small cell lung cancer, regardless of prior treatments. 

Selpercatinib May be an Effective NSCLC Treatment 

Treatment with aumolertinib led to improved progression free survival (PFS) and duration of response (DOR) in patients with advanced non-small cell lung caner (NSCLC) with epidermal growth factor receptor (EGFR), compared with gefitinib (Iressa), according to data presented during the 

“Based on these results, we will pursue discussions with global regulatory authorities; we anticipate our development approach will facilitate a markedly less costly global access pricing structure,” said Shun Lu, from the Shanghai Lung Cancer Center, Shanghai Chest Hospital at Shanghai JiaoTong University, in the presentation.

Aumolertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI) that has already been approved in China for patients with EGFR mutant NSCLC when disease has progressed and has favorable pharmacologic properties that inhibit EGFR sensitizing and resisting mutations.

This phase 3 trial assessed the safety and efficacy of treatment with aumolertinib compared to gefitinib in 429 patients across China who had previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R. Patients were randomly assigned to received either aumolertinib, once per day at 110mg (n= 214; median age, 59 years), or gefitinib, once per day at 250mg (n = 215; median age, 62 years). Researchers had a primary endpoint of (PFS), and secondary endpoints of overall survival (OS), objective response rate (ORR), DOR and safety. With 262 PFS events the study had 90% power to detect PFS (HR = 0.67).

Median PFS was significantly prolonged with aumolertinib at a median of 19.3 months (HR = 0.46; 95% CI, 17.8-20.8; 

 < 0.0001) compared with gefitinib at 9.9 moths (HR = 0.46; 95% CI, 8.3-12.6; 

Median DOR followed a similar trend and was also significantly prolonged by aumolertinib at 18.1 months (HR = 0.38; 95% CI, 15.2-NA; 

 < 0.0001) compared with gefitinib at 8.3 months (HR = 0.38; 95% CI, 6.9-11.1; 

 < 0.0001). ORR was 73.8% with aumolertinib and 72.1% with gefitinib. And median overall survival was not reached.

Although aumolertinib was a longer treatment time compared to gefitinib, 463 days versus 254 days, side effects such as rash, diarrhea, alanine aminotransferase/ aspartate aminotransferase increase were less likely in that group.

The most common adverse events included alanine aminotransferase increased (29.4% in the aumolertinib arm vs 55.8% in the gefitinib arm), aspartate aminotransferase increased (29.9% vs 54%, respectively), rash (23.4%, vs 41.4%), diarrhea (16.4% vs 35.8%) and creatine phosphokinase (CPK) increased (35.5% vs 9.3%).

Additionally, aumolertinib was also associated with CPK increased, platelet count decrease and neutrophil count decrease.

Further research evaluating aumolertinib with other treatments is either ongoing or planned, Lu noted.

Lu S, Dong X, Jian H, et al. Randomized Phase III Trial of Aumolertinib (HS-10296, Au) Versus Gefitinib (G) as First-Line Treatment of Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) and EGFR Exon 19 Del or L858R mutations (EGFRm). 

Treatment with aumolertinib led to improved progression free survival and duration of response in patients with advanced non-small cell lung caner with epidermal growth factor receptor, compared with gefitinib.

Aumolertinib Extends PFS and Duration of Response in EGFR+ Non–Small Cell Lung Cancer

In the phase 1/2 ARROW study, pralsentinib (Gavreto) was found to be well-tolerated and showed durable responses as treatment of patients with 

 fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.

“These data are real important because it supports the importance of early biomarker testing for all patients with metastatic NSCLC prior to treatment initiation to inform optimal healthcare decisions,” said Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano in Italy and head of the division of early drug development at the European Institute of Oncology in Italy, at the 2021 virtual ASCO Annual Meeting about updated data from the ARROW trial.

The phase 1/2 study was conducted at 84 sites in 13 countries. In particular, the safety population for this study included 233 patients with 

 fusion-positive NSCLC and 238 patients with other RET-altered solid tumors. In particular, 216 patients (median age, 60 years; 48% men) with 

fusion-positive NSCLC had measurable disease.

Originally patients who were treatment-naïve were not eligible, which was a requirement that was later removed by a protocol amendment. There were 25 patients who were enrolled after this eligibility revision (median age, 54 years; 44% men).

The study had a primary endpoint of objective response rate (ORR)Follow-up was conducted for a median of 17.1 months.

For the 216 patients who received pralsentinib and were 

 fusion-positive, the ORR was 69% (95%, CI, 62-75), DCR was 92% (95%, CI; 87-95), CBR was 77% (95%, CI; 71-82) and median DoR was 22.3 months (95%, CI; 15.1-not reached).

In the post-eligibility population with 25 patients, the ORR was 88% (95% CI, 69-98), CBR was 88% (95% CI, 69-98), DCR was 96% (95% CI, 80-100). In addition, median DoR and median PFS was not reached.

“The most important observation is that in the expansion cohort of real-world and first-line treatment of (non-small cell lung cancer) patients with 

fusion-positive tumor, the overall response rate was 88%, providing support for RET inhibitor as a first-line standard of care because the response rate was better in this population (with) respect to the previous eligibility criteria population,” Curigliano said.

The median duration of response in patients with prior platinum-based chemotherapy was 22.3 months (95% CI, 15.1-not reached). Curigliano added that it was too early to analyze data regarding the duration of response in treatment-naïve patients.

Overall, 26 patients (6%) out of 471 patients in the entire study discontinued treatment due to treatment-related adverse events. In all tumor types, 15% of patients had treatment-related neutropenia leading to treatment interruption whereas 14% had neutropenia from the treatment which resulted in a dose reduction. Less than 1% of patients discontinued treatment from treatment-related neutropenia.

“It means that pralsentinib was very well tolerated,” Curigliano said.

Curigliano, G, Gainor JF, Griesinger F, et al. Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: Update from the ARROW trial. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 9089.

In the phase 1/2 ARROW study, pralsentinib was found to be well-tolerated and showed durable responses as treatment of patients with RET fusion-positive non-small cell lung cancer, including those who were not eligible for platinum-based therapy.







Pralsentinib Demonstrates Tolerability and Elicits Durable Responses in RET Fusion-Positive NSCLC

Nivolumab (Opdivo) plus cabozantinib (Cabometyx) reportedly improved health-related quality of life (HRQoL) for patients with advanced renal cell carcinoma when compared to treatment with sunitinib (Sutent), according to an exploratory analysis of the phase 3 CheckMate 9ER trial presented at the 2021 ASCO Genitourinary Cancer Symposium.

Moreover, patients treated with the combination experienced a delay in deterioration and a significant decreased risk for confirmed deterioration in HRQoL scores, including disease-related kidney cancer symptoms.

“These results indicate that the superior clinical efficacy of (nivolumab plus cabozantinib) over (sunitinib) is accompanied by the additional benefit of better HQoL,” the researchers wrote. “Moreover, the HRQoL outcomes also support the acceptable tolerability profile of the (nivolumab plus cabozantinib) combination for patients with advanced HRQoL.”

In the CheckMate 9ER trial, after a median follow-up of 18.1 months, nivolumab plus cabozantinib demonstrated superior progression free survival (hazard ratio [HR], 0.51; 

 <.0001), compared with sunitinib, in patients with advanced RCC with a clear cell component.

In their presentation, the researchers investigated patient-reported HRQoL outcomes further, including overall between-group comparisons of treatment groups and time to confirmed deterioration outcomes.

“In addition to the clinical outcomes, analyses of HRQoL, including time to confirmed deterioration in patient-reported outcome (PRO) scores may provide important insights for clinicians to assess the benefit/risk profile of potential new treatment regimens,” the researchers wrote.

To be eligible for the phase 3 trial, patients had to have previously untreated, advanced or metastatic RCC; a clear cell component; and any International Metastatic RCC Database Consortium (IMDC) risk. Patients were then stratified by IMDC risk score, tumor PD-L1 expression, and geographic region.

In total, patients were randomized 1:1 to receive either nivolumab at 240 mg IV every 2 weeks plus oral cabozantinib 40 mg daily (n = 323) or oral sunitinib at 50 mg daily for 4 weeks on, 2 weeks off (n = 328), until disease progression or toxicity.

PRO instruments were administered before treatment, and included Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and the 3-level version of the EQ-5D (EQ-5D-3L). PRO completion rates for both arms were at 93% or more at baseline, and completion rates remained at 80% or more through week 91.

Longitudinal score changes from baseline in FKSI-19 total score and FKSI-19 disease-related symptom (DRS) scores favored nivolumab plus cabozantinib, compared to sunitinib, with an overall mean change from baseline of 2.90 (-0.51 vs -3.40; 

Mean change in EQ-5D-3L utility index and visual analog scale (VAS) scores also favored nivolumab plus cabozantinib, showing significant change through treatment with an overall change of 0.05 (-0.02 vs -0.07; 

 = .0011), respectively, with the combination versus sunitinib.

There was also a significant decreased risk of confirmed deterioration with nivolumab plus cabozantinib in FKSI-19 total score (HR, 0.64; 95% CI, 0.50-0.81; 

 = .0003) and FKSI-19 DRS score (HR, 0.62; 95% CI, 0.46-0.82; 

Cella D, Choueiri t, Blum S, et al. Patient-Reported Outcomes of Patients with Advanced Renal Cell Carcinoma Treated with First-Line Nivolumab Plus Cabozantinib Versus Sunitinib: the CheckMate 9ER Trial. Presented at: 2021 ASCO Genitourinary Cancer Symposium; February 11-13, 2021; Virtual. Abstract 285.

Nivolumab plus cabozantinibreportedly improved health-related quality of life  for patients with advanced renal cell carcinoma when compared to treatment with sunitinib.








Colleen Moretti | Authors

Articles

Selpercatinib May be an Effective NSCLC Treatment

Aumolertinib Extends PFS and Duration of Response in EGFR+ Non–Small Cell Lung Cancer

Pralsentinib Demonstrates Tolerability and Elicits Durable Responses in RET Fusion-Positive NSCLC

Nivolumab and Cabozantinib Combo Found to Improve Quality of Life for Patients with Advanced RCC