Jamie Cesanek

Overall survival (OS) was not improved with alectinib (Alecensa) in patients with treatment-naïve, advanced ALK-positive non-small cell lung cancer (NSCLC), compared to crizotinib (Xalkori).

However, the data, which were presented during the 2021 ASCO Annual Meeting, may be confounded since 78.8% of patients who received crizotinib received alectinib initially.

In the primary analysis of the phase 3 randomized, open-label J-ALEX (JapicCTI-132316) study, alectinib demonstrated better progression-free survival (PFS) than crizotinib (HR = 0.34, 99.7% CI, 0.17-0.71; 

 = .0001). Median PFS was not reached with alectinib, compared to 10.2 months with crizotinib. Additional data from a data cut-off in June 2018 continued demonstrating better PFS for alectinib than crizotinib (HR = 0.37; 95% CI, 0.26-0.52). In the final analysis, investigators sought to examine OS data after a minimum of 5 years of follow up.

“In this final analysis, from J-ALEX, prolongation of OS in the alectinib arm was not observed compared to crizotinib,” said Hiroshige Yoshioka, MD, of Kansaid Medical University Hospital, in a presentation of the findings. “However, median OS was not reached in either treatment arm. This OS result may have been confounded by crossover.”

Patients were randomized 1:1 to receive either alectinib (300 mg twice daily) or crizotinib (250mg twice daily) until progressive disease (PD), unacceptable toxicity, withdrawal or death. Treatment crossover between arms was permitted after withdrawal.

Patients were eligible for the study if they were 20 years of age or older, had stage 3B, 4 or recurrent NSCLC, had ALK-positive disease, an ECOG score of 0-2, had ≥ 1 measurable lesion assessed by investigator and had received 1 or less prior chemotherapy. Treated or asymptomatic brain metastases were allowed.

At a median follow-up of 68.6 months in the alectinib arm and 68 months in the crizotinib arm, deaths occurred in 40.8% and 39.4% of patients, respectively. Five-year survival rates for alectinib-treated patients were 60.85% compared to 64.11% in crizotinib-treated patients.

The global ALEX study, in which no major subsequent ALK TKIs as opposed to the J-ALEX study, including treatment crossover, demonstrated clinically meaningful OS improvement from alectinib compared to crizotinib in treatment-naïve, advanced ALK-positive NSCLC. OS data remain immature (HR = 0.67; 95% CI 0.46-0.98).

Yoshioka H, Hida T, Nokihara H, et al. Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC). 

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Overall survival was not improved with alectinib in patients with treatment-naïve, advanced ALK-positive non-small cell lung cancer, compared to crizotinib. 

OS Not Improved by Alectinib in ALK-Positive NSCLC

Sustained overall survival (OS) and progression-free survival (PFS) benefits was confirmed following long-term treatment with durvalumab following chemoradation in patients with unresectable stage 3 non-small cell lung cancer (NSCLC) whose disease had not progressed after platinum-based concurrent chemoradiotherapy, according to 5-year follow-up data from the phase 3 PACIFIC (NCT02125461) trial.

“(These study results establish) a new benchmark for the standard of care in the unresectable stage 3 non-small-cell lung cancer setting,” said lead study author David R. Spigel, MD, of the Sarah Cannon Cancer Institute, while presenting the findings during the 2021 ASCO Annual Meeting.

Earlier data from the phase 3 PACIFIC trial, 

, demonstrated how treatment with durvalumab significantly improved OS versus placebo among patients. 

The trial comprised 713 patients randomized 2:1 to receive either study drug (n = 476) at 10 mg/kg q2w or placebo (n = 237) q2w for up to 12 months.

Eligible patients must have had unresectable stage 3 NSCLC without progression after definitive platinum-based cCRT (≤2 cycles), a WHO PS score of 0 or 1, archived pre-cCRT tumor tissue for PD-L1 testing (if available) and been 18 years or older. PD-L1 enrollment status was not required for enrollment in the trial.

Here, Spigel and colleagues presented 5-year updated data from the randomized, double-blind trial. The OS and PFS outcomes were assessed approximately 5 years after the last patient was randomized. Data cutoff was January 11, 2021.

At a median follow-up of 34.2 months, updated median 5-year OS was 47.5 months in the arm that received durvalumab and 29.1 months in those who received placebo (HR = 0.72; 95% CI, 0.59-0.89). Moreover, median 5-year PFS in the durvalumab arm was 16.9 months and 5.6 months in the placebo arm (HR = 0.55; 95% CI, 0.45-0.68).

Of note, an estimated 42.9% of patients randomized to durvalumab remain alive at 5 years as opposed to 33.4% of patients who received a placebo. And approximately 33.1% of durvalumab-treated patients remain alive without disease progression compared to 19% of the placebo group.

The last patient completed treatment in May 2017. Since then, 58.8% of randomized patients died (55.5% who had received durvalumab and 65.4% who had received the placebo).

Spigel concluded noting that the regimen from the PACIFIC trial is being investigated in combination with other chemoradiotherapy regimens as well as other agents following chemoradiotherapy.

Spigel DR, Faivre-Finn C, Elaine Gray J, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial. 

Sustained overall survival and progression-free survival benefits was confirmed following long-term treatment with durvalumab following chemoradation in patients with unresectable stage 3 non-small cell lung cancer whose disease had not progressed after platinum-based concurrent chemoradiotherapy. 

Long-Term Survival Benefit with Durvalumab in NSCLC Confirmed in Updated Findings

Results from the phase 3 ARAMIS trial revealed that darolutamide (Nubeqa) remained well-tolerated with a highly favorable safety profile compared with placebo and androgen deprivation therapy in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to data presented at the 2021 ASCO Annual Meeting.

“Almost all patients treated with darolutamide were able to receive the full planned dose with no change between double-blind and open-label periods,” said Karim Fizazi, MD, medical oncologist at Gustave Roussy, while presenting the findings. “And the majority of patients who required dose modifications subsequently reescalated to the full dose.”

ARAMIS was a double-blind and randomized phase 3 trial (NCT02200614) of darolutamide (Nubeqa) in men with nmCRPC to examine the potential of second-generation androgen receptor inhibitors (ARI), which could prolong metastasis-free survival with minimal adverse events (AE). The trial was unblinded at primary analysis, after which all patients could receive open label darolutamide.

Patients were randomized 2:1 to receive either darolutamide (n = 955) or a placebo (n = 554) with androgen deprivation therapy, with assessments of tolerability every 16 weeks. Median time on treatment was 18.5 months in the darolutamide double-blind (DB) group, 11.6 months in the placebo DB group, 25.8 months in the darolutamide DB and open label (OL) group and 11 in the placebo crossover to darolutamide OL group. Pharmacodynamic modeling was used to examine the association between maximum prostate-specific antigen (PSA) decline and overall survival (OS) at 2 years.

Darolutamide was well-tolerated over the DB and OL periods (98.9% of patients received full-planned dose) and majority of patients with dose modifications were able to resume the planned dose (darolutamide 89.6%, placebo 89.7%). The discontinuation rate due to disease progression was lower in the darolutamide group compared to the placebo group during the DB period (12.5% vs 35.3%). It remained a similar number with extended treatment during the DB and OL period (12.6%). Discontinuation due to AE increased slightly from the DB period (9%) to the DB and OL period (10.5%).

Pharmacodynamic modeling showed a positive association between OS and maximum PSA decline (defined as a ≥90% decline from baseline), indicating that long-term treatment with darolutamide delays disease progression and extends survival.

“Landmark sensitivity analysis of patients with PSA data at week 16 confirmed a positive association between PSA declines at week 16 and subsequent outcomes including overall survival,” said Fizazi. “Adjusting the landmark analyses for baseline covariates had little impact on best effect on overall survival.”

Treatment-emergent adverse events (TEAE) led to permanent discontinuation in 85 DB darolutamide-treated patients (8.9%), 48 DB placebo-treated patients (8.7%), 100 DB and OL darolutamide-treated patients (10.5%) and 8 in the DB-darolutamide OL crossover group (4.7%). The most common TEAE included transaminase increases, blood creatinine increase or neutropenia; deep vein thrombosis, hypertension, hypotension, peripheral ischemia or vasculitis; and abdominal discomfort/distension/pain, diarrhea, gastritis, nausea or small-intestine perforation.

Fizazi K, Shore ND, Raymond Smith M, et al. Darolutamide (DARO) tolerability from extended follow up and treatment response in the phase 3 ARAMIS trial. 

Men with nonmetastatic castration-resistant prostate cancer tolerated treatment with darolutamide well, according to findings from the phase 3 ARAMIS trial.

Jamie Cesanek | Authors

Articles

OS Not Improved by Alectinib in ALK-Positive NSCLC

Long-Term Survival Benefit with Durvalumab in NSCLC Confirmed in Updated Findings

Darolutamide Shows Favorable Safety Profile in Patients With Nonmetastatic Prostate Cancer