ESMO 2014: New Data on First- and Second-Line ALK Inhibition in NSCLC Patients

Overall and intracranial efficacy results and time to symptom deterioration in the PROFILE 1014 study; Alectinib’s activity in crizotinib pre-treated ALK-rearranged NSCLC

Two presentations at Proffered Papers Session on Metastatic Non-small cell lung cancers (NSCLC) during the ESMO 2014 Congress (Madrid, Spain) discussed the use of crizotinib in the first-line setting and efficacy of a second-generation ALK inhibitor, alectinib, in patients with crizotinib-resistant disease. Patients with NSCLC and ALK gene rearranged tumours show dramatic and sustained responses to treatment with ALK inhibitors, with crizotinib being the first-in-class ALK inhibitor. Unfortunately, resistance to crizotinib invariably develops and the researchers are trying to address it by next generation ALK inhibitors.

First-line crizotinib vs pemetrexed/platinum chemotherapy in patients with advanced ALK-positive non-squamous NSCLC

The efficacy of first-line crizotinib in improving progression-free survival (PFS) compared with standard pemetrexed/platinum chemotherapy in patients with advanced ALK-positive NSCLC was established in the phase III PROFILE 1014 study which included 343 patients. The results were presented by Dr Tony Mok earlier this year during the ASCO 2014 Annual Meeting. Dr Benjamin Solomon from the Peter MacCallum Cancer Centre, Melbourne, Australia, reported additional data from this study during the ESMO 2014 Congress (abstract 1225O).

Crizotinib is an oral small-molecule tyrosine kinase inhibitor that targets ALK, ROS1, and MET. It is approved for advanced ALK-positive NSCLC. The PROFILE 1014 is the first prospective, randomised phase III trial to compare the efficacy and safety of ALK-targeted therapy with standard chemotherapy for advanced ALK-positive NSCLC in the first-line setting.

Clinical outcomes (overall and intracranial efficacy, lung cancer symptoms) with crizotinib vs standard chemotherapy as first-line treatment were compared in this ongoing multicentre study in the whole patient population and in patient subgroups.

Patients with previously untreated advanced non-squamous ALK-positive NSCLC were randomised 1:1 to crizotinib (172 patients) or pemetrexed plus cisplatin or carboplatin (171 patients). Continuation of/crossover to crizotinib after progressions of disease per independent radiology review was allowed for patients randomised to both arms.

The primary endpoint was PFS per independent radiology review. Secondary endpoints included overall survival (OS), intracranial time to progression, time to deterioration in symptoms of chest pain, dyspnoea, or cough, and safety.

The study met its primary objective: crizotinib was superior to chemotherapy in prolonging PFS (median 10.9 vs 7.0 months; hazard ratio - HR 0.45, p < 0.0001). The PFS benefit with crizotinib was observed in most patient subgroups analysed. Median PFS was 6.9 months with pemetrexed/cisplatin (HR 0.49, p < 0.0001) and 7.0 months with pemetrexed/carboplatin (HR 0.44, p < 0.0001).

Objective responses with crizotinib were rapid and durable when compared with chemotherapy (74% vs 45%). With 68% of patients still in follow-up, median OS was not reached in either arm. There was a numerical improvement in OS in the crizotinib arm (HR 0.82, p = 0.361).

Analysis was not adjusted for the potentially confounding effects of crossover; 70% of patients in the chemotherapy arm received crizotinib after progression.

The intracranial time to progression HR for crizotinib vs chemotherapy was 0.60 (non-significant difference; only around 15% of patients had intracranial events). In patients with baseline brain metastases, first-line crizotinib showed a numerical improvement in intracranial time to progression and demonstrated a statistically significant improvement in intracranial disease control rate at 12 (p = 0.0003) and 24 weeks (p = 0.006).

The time to deterioration in symptoms was around four times longer in the crizotinib arm than in the chemotherapy arm (median 2.1 months vs 0.5 months; HR 0.62; p = 0.0004).

The most common adverse events of any cause with crizotinib were vision disorder and gastrointestinal symptoms. Adverse events with pemterexed/platinum chemotherapy were consistent with those previously reported in unselected NSCLC.

The authors concluded that crizotinib showed significant improvements in PFS and the time to deterioration in symptoms vs pemetrexed/platinum chemotherapy, a numerical improvement in intracranial time to progression, and an acceptable safety profile, establishing crizotinib as the standard of care for patients with treatment-naive advanced ALK-positive non-squamous NSCLC.

The study was sponsored by Pfizer.

Antitumour activity of alectinib in crizotinib pre-treated ALK-rearranged NSCLC

Alectinib showed promising response, including patients with brain metastases, and good tolerability in crizotinib pre-treated NSCLC patients, according to the updated efficacy and safety data from the JP28927 study. The results were presented by Dr Takashi Seto from the National Kyushu Cancer Center, Fukuoka, Japan during the ESMO 2014 Congress (abstract 1224O).

Alectinib is a CNS-penentrant, highly selective ALK inhibitor. It is approved in Japan since 7 April 2014 and designated by FDA as a breakthrough therapy. ALEX is a global randomised, phase III, first-line study of alectinib vs crizotinib that currently recruits treatment-naive patients with ALK-positive advanced NSCLC.

The JP28927 is a clinical pharmacological study to evaluate the bioequivalence of alectinib in ALK-rearranged NSCLC patients with or without previous treatment with ALK inhibitor. The results for bioequivalence, food effect, efficacy and safety were reported earlier this year at ASCO 2014 Annual Meeting.

ALK-rearranged NSCLC patients had to discontinue treatment from crizotinib, a first generation ALK inhibitor, because of drug resistance or intolerance. During the ESMO 2014, the investigators presented updated efficacy and safety data for alectinib in 28 crizotinib pre-treated NSCLC patients included in this study.

As of 11 January, 2014, median follow-up duration was 141 days and 21 patients continued treatment with alectinib without progressive disease. Among 24 patients with target lesions, tumour shrinkage of more than 30% was observed in 18 patients. Confirmed response rate was 58.3% and disease control rate was 83.3 % as assessed by study investigators.

From 19 patients who had brain metastases at baseline, 13 (including 4 patients without prior brain irradiation) were still on study treatment without disease progression.

The safety profile was favourable and continued the same trend previously reported. No patients discontinued study treatment for a safety reason. Gastrointestinal and visual disorders, characteristic for crizotinib treatment, were mild and not so frequent with alectinib.

The authors concluded that their findings suggest that alectinib is a novel therapeutic option for crizotinib pre-treated ALK-rearranged NSCLC.

The study was sponsored by Chugai Pharmaceutical Co., Ltd.

Defining and refining the ALK treatment paradigm in NSCLC

Dr Alice Shaw, who discussed the results of both studies, said that for patients with advanced ALK-positive NSCLC crizotinib represents a standard first-line therapy. However, it has modest activity in the CNS. Next generation ALK inhibitors, like alectinib and ceritinib, are active in patients who relapse on crizotinib, and represent a new standard of care.

Further studies are needed to determine the optimal sequencing of ALK inhibitors. The open questions, according to Dr Shaw, are:

  • should a next generation ALK inhibitor be used as first-line therapy;
  • which ALK inhibitor should be used in the second-line setting in term of CNS efficacy, tolerability, and resistance  mechanism; 
  • is there a role for a third-line ALK inhibitor in term of CNS disease and resistance mechanism.

References

1225O - Overall and intracranial (IC) efficacy results and time to symptom deterioration in PROFILE 1014: 1st-line crizotinib vs pemetrexed - platinum chemotherapy (PPC) in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC)

1224O - Anti-tumor activity of alectinib in crizotinib pre-treated ALK-rearranged NSCLC in JP28927 study