Avelumab Plus Lorlatinib Active in ALK+ NSCLC

Avelumab plus lorlatinib showed clinical activity with tolerable toxicities among patients with ALK-mutation–harboring non–small-cell lung cancer (ALK+ NSCLC), but avelumab plus crizotinib was not a promising treatment for non–ALK-driven NSCLC, according to findings from the phase Ib JAVELIN Lung 101 dose-finding study (abstract 9008), presented at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1–5 in Chicago.

“Avelumab plus lorlatinib treatment in heavily pretreated patients with ALK+ NSCLC showed a manageable safety profile with no dose-limiting toxicities,” reported lead study author Alice Tsang Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston. “Antitumor activity was promising.”

“Avelumab plus crizotinib treatment was not well-tolerated in patients with non–ALK-driven NSCLC, and no further development of this combination is planned,” she added.

ALK TKIs like crizotinib are a standard of care for patients with advanced ALK+ NSCLC, Shaw said. But mutations in ALK lead to TKI resistance in up to 25% of cases of crizotinib resistance and perhaps half of cases of resistance to second-generation ALK TKIs like ceritinib, alectinib, and brigatinib, Shaw said.

Lorlatinib is a third-generation, central nervous system–penetrating ALK TKI active against ALK TKI-resistance mutations.

Immune checkpoint inhibitors targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are clinically active in NSCLC and prolong some patients’ survival, but most patients do not benefit from anti–PD-1/PD-L1 immunotherapies because of primary resistance. “Patients with ALK+ NSCLC may be insensitive to checkpoint inhibitors,” Shaw said.

Avelumab is a human IgG1 antibody that targets PD-L1. It has shown single-agent antitumor activity against NSCLC.

The study authors hypothesized that ALK inhibitors like crizotinib and avelumab immune checkpoint inhibition might offer synergistic activity against non–ALK-driven NSCLC, while combining avelumab and lorlatinib might benefit patients with previously treated ALK+ NSCLC.

JAVELIN Lung 101 (ClinicalTrials.gov identifier: NCT02584634) was an open-label, multicenter dose-finding trial to assess the safety, tolerability, and antitumor activity of avelumab in combination with crizotinib and with lorlatinib. Two study groups were opened for enrollment. Patients enrolled into group A (n = 12) had advanced ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification or exon 14 skipping, treatment with at least one prior line of systemic therapy, and no prior treatments targeting immune checkpoint inhibition. They received an initial avelumab dosage of 10 mg/kg (1 h IV) every 2 weeks plus 250-mg twice-daily oral crizotinib.

Patients enrolled into group B (n = 28) had advanced ALK+ NSCLC without prior exposure to immune checkpoint inhibitors and no symptomatic brain metastases. They received the same initial dose of avelumab (10 mg/kg IV every 2 weeks) plus 100 mg oral lorlatinib once daily.

Avelumab plus lorlatinib was not associated with any dose-limiting toxicities (DLTs). Five patients (42%) in the avelumab-plus-crizotinib group experienced DLTs, three of whom had more than one DLT. In this group, DLTs included elevated ALT, elevated ST, febrile neutropenia, hepatitis, rash, and QT prolongation. Three patients in the avelumab-plus-lorlatinib group were not evaluable for DLTs, Shaw reported.

Nearly all of the patients experienced adverse events (AEs) of some grade (100% in the avelumab-plus-crizotinib group, 58% of which were grade ≥ 3 AEs, and 96% of patients in the avelumab-plus-lorlatinib group, 53.6% of which were grade ≥ 3 AEs). Serious AEs occurred in 42% of patients in the avelumab-plus-crizotinib group, including treatment-related febrile neutropenia, hepatitis, and rash (1 patient each) and 39% of patients in the avelumab-plus-lorlatinib group, including treatment-related pneumonitis (2 patients) and increased AST, delirium, dyspnea, and pericardial effusion (1 patient each).

The most common grade ≥ 3 AE in the avelumab-plus-crizotinib group was elevated ALT (2 patients; 16.7%). The most common grade ≥ 3 AE in the avelumab-plus-lorlatinib group was hypertriglyceridemia (4 patients; 14%).

No complete tumor responses were reported for the avelumab-plus-crizotinib (ALK-negative) group, and only 2 patients (16.7%) had partial tumor responses, for an objective response rate (ORR) of 16.7%.

One patient in the avelumab-plus-lorlatinib (ALK+) group experienced a complete tumor response and 12 more (43%) experienced partial responses, for an ORR of 46.4%.

Commenting on the study, Apar K. Ganti, MD, MS, from the Division of Oncology-Hematology at the
University of Nebraska Medical Center, Omaha, said, "While the combination of avelumab and lorlatinib showed promising response rates in ALK-positive lung cancers, the contribution of each agent is unclear, especially since lorlatinib is an active agent in these tumors. Not surprisingly, this combination did not have any effect in ALK-negative lung cancers."