Phase 3 Trials Show Superiority of Targeted Treatments Over Chemotherapy in Oncogene-Addicted NSCLC

December 2023, Vol 14, No 6

Madrid, Spain—Results from 3 phase 3 clinical trials demonstrated the superiority of targeted therapies over conventional chemotherapy in patients with oncogene-addicted non–small cell lung cancer (NSCLC), including ALK-positive advanced NSCLC; EGFR exon 20 insertion-mutation–positive, newly diagnosed or advanced NSCLC; and advanced RET fusion–positive NSCLC. These findings were reported during the European Society for Medical Oncology Congress 2023.

ALINA: Alectinib for ALK-Positive NSCLC

At a prespecified interim analysis, alectinib (Alecensa) demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) compared with platinum-based chemotherapy in patients with completely resected ALK-positive NSCLC, meeting the primary end point of the phase 3 ALINA study.1

Adjuvant treatment with alectinib was associated with a significant improvement in DFS compared with platinum-based chemotherapy at a median follow-up of approximately 28 months, with favorable results for alectinib observed in both the stage II-IIIA population (n=231; hazard ratio [HR], 0.24; P<.0001) and the intent-to-treat (ITT) stage IB-IIIA population (n=257; HR, 0.24; P<.0001), reported Benjamin Solomon, MBBS, PhD, FRACP, Medical Oncologist, Peter MacCullum Cancer Centre, Melbourne, Australia; and Honorary Professor, Oncology, The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria.

Based on these results, “adjuvant alectinib represents an important new treatment strategy for patients with resected, stage IB-IIIA ALK-positive NSCLC,” he said.

Up to 40% of patients with NSCLC are diagnosed with resectable disease, and despite treatment, the risk for disease recurrence remains high, Dr Solomon explained. ALK rearrangements are found in 4% to 5% of patients with NSCLC; typically, in younger patients (median age at diagnosis, 55 years) and nonsmokers, and are associated with a high risk for brain metastases.

“For patients with resectable ALK-positive NSCLC, the current standard-of-care after surgery remains adjuvant platinum-based chemotherapy; immunotherapy is not recommended,” said Dr Solomon.

ALINA Study Details

ALINA, an open-label, global study, enrolled 257 patients with completely resected, stage IB (≥4 cm)-IIIA, ALK-positive NSCLC. Patients were randomized in a 1:1 ratio to receive either oral alectinib 600 mg twice daily or up to four 21-day cycles of intravenous platinum-based chemotherapy.

The median DFS was not reached in the alectinib arm and was 44.4 months in the chemotherapy arm. In the ITT population, median DFS was not reached with alectinib versus 41 months with chemotherapy. Two-year DFS rates were 93.8% in the alectinib arm versus 63.0% in the chemotherapy arm in the stage II-IIIA population, and 93.6% versus 63.7%, respectively, in the ITT population.

A clinically meaningful central nervous system (CNS) DFS benefit was also observed in the ITT population (HR, 0.22; 95% confidence interval [CI], 0.08-0.58). Overall survival (OS) data were immature at the time of data cutoff.

No unexpected safety findings were observed. Grade 3/4 adverse events (AEs) were reported in 30% of patients receiving alectinib and 31% receiving chemotherapy. There were no grade 5 AEs in either treatment arm.

PAPILLON: Amivantamab for EGFR Exon 20 Insertion–Mutated NSCLC

In patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion-mutation–positive NSCLC, amivantamab (Rybrevant) plus carboplatin and pemetrexed (Alimta) led to a clinically meaningful and statistically significant improvement in progression-free survival (PFS) compared with carboplatin and pemetrexed alone, thus meeting the primary end point of the phase 3 PAPILLON study.2

The safety profile of the combination regimen was comparable to that of each agent alone.

These data are the first to demonstrate a clinically meaningful benefit in a randomized trial in this population, and support the amivantamab and chemotherapy combination as “the new standard of care for first-line EGFR exon 20 insertion, advanced NSCLC,” said lead investigator Nicolas Girard, MD, PhD, Chair, Department of Medical Oncology, and Head, Thoracic Oncology, L’Institut du Thorax Curie-Montsouris, Paris, France.

Amivantamab has already been FDA approved for the treatment of patients with advanced NSCLC with EGFR exon 20 insertions who have had disease progression during or after platinum-based chemotherapy.

“Outcomes in newly diagnosed EGFR exon 20 insertion, advanced NSCLC are historically poor,” he said. “Reported median [OS] has ranged from 16 to 24 months, with a 5-year OS rate of 8.” Platinum-based chemotherapy is the standard of care, but has limited efficacy, and checkpoint inhibitors have failed to show benefit in this setting.

PAPILLON Study Details

In the open-label PAPILLON study, 308 patients with treatment-naïve advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy were randomized to receive either intravenous amivantamab plus carboplatin and pemetrexed or chemotherapy alone. At data cutoff (May 3, 2023), treatment was ongoing in 46% of the amivantamab/chemotherapy arm versus only 15% of the chemotherapy-alone arm.

At a median follow-up of 14.9 months, median PFS was 11.4 months in the amivantamab/chemotherapy arm versus 6.7 months in the chemotherapy-alone arm, representing a 60% reduction in the risk for disease progression or death with amivantamab (HR, 0.395; P<.0001). The 12-month PFS rates were 48% and 13%, respectively. The 18-month PFS rates (31% vs 3%, respectively) demonstrated sustained and increasing benefit to amivantamab plus chemotherapy, said Dr Girard.

The median PFS after first subsequent therapy (PFS2) was not reached in the amivantamab/chemotherapy arm versus 17.2 months in the chemotherapy-alone arm (HR, 0.493; P=.01). The longer PFS2 with amivantamab supports its use in the first line, Dr Girard noted.

An interim OS analysis showed a trend favoring amivantamab/chemotherapy, with a reduction in the risk for death ≥30% (HR, 0.675; P=.106).

The predominant AEs associated with amivantamab/chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab due to AEs.

LIBRETTO-431: Selpercatinib for RET Fusion–Positive Disease

An open-label randomized study (LIBRETTO-431) showed the superiority of first-line selpercatinib (Retevmo) compared with the prevailing standard of care (PD-1 inhibitor plus chemotherapy) in patients with advanced or metastatic RET fusion–positive NSCLC.3

At a preplanned interim efficacy analysis at a median follow-up of 19 months, median PFS was more than double in the selpercatinib arm compared with patients randomized to platinum and pemetrexed chemotherapy with or without pembrolizumab (Keytruda)—24.8 versus 11.2 months (HR, 0.465; P<.001), respectively, reported Herbert H. F. Loong, MBBS(HK), PDipMDPath(HK), MRCP(UK), FRCP, FHKCP, FHKAM (Medicine), Clinical Associate Professor, Medical Oncology, Department of Clinical Oncology, and Deputy Medical Director, Phase 1 Clinical Trials Centre, The Chinese University of Hong Kong. The benefit of selpercatinib on PFS in the ITT population closely mirrored that observed in the ITT-pembrolizumab population (HR, 0.482; P<.001).

“Selpercatinib should be considered a first-line standard of care in RET fusion–positive advanced NSCLC,” Dr Loong concluded. “These results reinforce the importance of genomic testing to identify RET fusions at the time of diagnosis to inform initial therapy.”

LIBRETTO-431 Study Details

The phase 3 LIBRETTO-431 study enrolled 261 patients with advanced or metastatic RET fusion–positive NSCLC who had received no previous systemic therapy for metastatic disease. Patients were randomized in a 2:1 ratio to receive either selpercatinib or chemotherapy with cisplatin or carboplatin plus pemetrexed with or without pembrolizumab (at the investigator’s discretion) as initial treatment in the advanced or metastatic stage. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment; 42 patients crossed over to selpercatinib during the study. A total of 212 patients underwent randomization in the ITT-pembrolizumab population. Approximately 20% of patients had brain metastases upon enrollment.

In patients with measurable CNS disease at baseline, selpercatinib demonstrated an improved intracranial PFS. Time to CNS progression was delayed with selpercatinib. Among patients without CNS metastases at baseline, the risk for CNS progression at 12 months was 1.1% in the selpercatinib arm versus 14.7% in the control arm (HR, 0.17; 95% CI, 0.04-0.69), and among those with CNS metastases at baseline, this risk was reduced from 33.3% in the control arm to 25.7% in the selpercatinib arm (HR, 0.61; 95% CI, 0.19-1.92).

“It is reasonable to say that not only is selpercatinib active in patients who have brain metastases but there is evidence of a preventive effect of development of brain metastases in patients with RET fusion–positive NSCLC,” Dr Loong said.

AEs that occurred with selpercatinib and control treatment were consistent with those previously reported.


  1. Solomon BJ, Ahn JS, Dziadziuszko R, et al. ALINA: efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S1295. Abstract book of the ESMO Congress 2023. doi:10.1016/j.annonc.2023.10.051
  2. Girard N, Park K, Tang K, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): primary results from PAPILLON, a randomized phase III global study. Ann Oncol. 2023;34(suppl 2):S1304. Abstract book of the ESMO Congress 2023. doi:10.1016/j.annonc.2023.10.060
  3. Loong HHF, Goto K, Solomon BJ, et al. Randomized phase III study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC. Ann Oncol. 2023;34(suppl 2):S1303. Abstract book of the ESMO Congress 2023. doi:10.1016/j.annonc.2023.10.059

Related Articles