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. 2024 Sep 1;4(9):2553-2564.
doi: 10.1158/2767-9764.CRC-24-0338.

Long-Lasting Response to Lorlatinib in Patients with ALK-Driven Relapsed or Refractory Neuroblastoma Monitored with Circulating Tumor DNA Analysis

Torben Ek #  1   2 , Raghda R Ibrahim #  2   3 , Hartmut Vogt  4 , Kleopatra Georgantzi  5   6 , Catarina Träger  6   7   8 , Jennie Gaarder  9   10 , Anna Djos  9 , Ida Rahmqvist  2   3 , Elisabeth Mellström  1   2   3 , Fani Pujol-Calderón  2   3 , Christoffer Vannas  11   12 , Lina Hansson  12 , Henrik Fagman  9   13 , Diana Treis  5   6 , Susanne Fransson  9   10 , Tobias Österlund  3   10   11 , Tzu-Po Chuang  14 , Bronte Manouk Verhoeven  6 , Anders Ståhlberg  3   10   11 , Ruth H Palmer  14 , Bengt Hallberg  14 , Tommy Martinsson  9 , Per Kogner  5   6 , Martin Dalin  1   2   3
Affiliations

Long-Lasting Response to Lorlatinib in Patients with ALK-Driven Relapsed or Refractory Neuroblastoma Monitored with Circulating Tumor DNA Analysis

Torben Ek et al. Cancer Res Commun. .

Abstract

Patients with anaplastic lymphoma kinase (ALK)-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here, we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35 to 61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single-agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA increased 9 and 3 months, respectively, before clinical detection of disease progression. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after 8 months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma.

Significance: We present five patients with ALK-driven relapsed or refractory neuroblastoma treated with lorlatinib as monotherapy. All patients responded to treatment, and four of them were alive after 3 to 5 years of follow-up. We performed longitudinal ctDNA analysis with ultra-deep sequencing of the ALK tyrosine kinase domain. We conclude that ctDNA analysis may guide treatment decisions in ALK-driven neuroblastoma, also when the disease is undetectable using standard clinical methods.

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Conflict of interest statement

A. Ståhlberg reports grants from the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement, Sweden’s Innovation Agency, the Sjöberg Foundation, Region Västra Götaland, and the Sarcoma patient organization research fund, the memorial fund of Elvira Trané; grants and personal fees from the University of Gothenburg; and personal fees from the Sahlgrenska University Hospital during the conduct of the study; as well as other support from Iscaffpharma, Simsen Diagnostics, and Tulebovaasta outside the submitted work; and a patent to simple, multiplexed, PCR-based barcoding of DNA for sensitive mutation detection using sequencing issued. P. Kogner reports personal fees from Recordati outside the submitted work. M. Dalin reports grants from the Wallenberg Centre for Molecular and Translational Medicine, the Swedish Childhood Cancer Fund, the Swedish Society for Medical Research, the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement, Sahlgrenska Academy at the University of Gothenburg, the Assar Gabrielsson Research Foundation, and Svensson’s Fund for Medical Research during the conduct of the study. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
Clinical response to lorlatinib in patients with ALK-driven relapsed or refractory neuroblastoma. Black arrows denote ongoing treatment or follow-up. *Germline ALK variant. CR, complete response; PR partial response.
Figure 2
Figure 2
ctDNA analysis using the NB-ALK sequencing panel. Pink areas denote parts of the ALK gene included in the panel. Recurrent mutations previously detected in neuroblastoma or associated with resistance to TKIs that are covered by the panel are shown; neuroblastoma hotspot mutations are bold. Angled numbers denote the range of ALK amino acid positions covered by each of the seven assays.
Figure 3
Figure 3
Lasting response to lorlatinib in a patient (patient 1) with relapsed neuroblastoma harboring ALK p.R1275Q. A, Chest computed tomography (top) and MIBG scans (bottom) at time of initial diagnosis, at relapse, and after 2 months of lorlatinib treatment. Red arrows denote tumors. B, Levels of ctDNA during and after lorlatinib treatment. ND, not detected. C, Chromogranin A. URL, upper reference limit (102 µg/L). NSE, urine VMA and urine HVA were within normal ranges at time of relapse and were therefore not further analyzed. HVA, homovanillic acid; VMA, vanillylmandelic acid.
Figure 4
Figure 4
Detection of relapse with ctDNA analysis 9 months prior to clinical presentation in a patient (patient 2) with ALK p.R1275Q-positive neuroblastoma treated with lorlatinib. A, MIBG scans. B, Levels of ctDNA. C, NSE. CS, Curie score; ND, not detected; TID, temozolomide, irinotecan and dinutuximab; URL, upper reference limit (16.3 µg/L).
Figure 5
Figure 5
Long-term response to lorlatinib in a patient (patient 4) with refractory ALK p.R1275Q-positive neuroblastoma. A, MIBG or 68Ga-DOTATATE scans at the time of diagnosis, after induction of chemotherapy, and after 5 months of lorlatinib treatment. Red arrows denote tumors. B, Levels of ctDNA. C, Plasma methoxy noradrenaline. ND, not detected; URL, upper reference limit (0.7 nmol/L).
Figure 6
Figure 6
Early detection of relapse and emergence of an HRAS p.Q61L mutation during lorlatinib treatment in a patient (patient 5) with ALK p.F1174L-positive neuroblastoma. A, MIBG scans at initial diagnosis, at the first relapse, after 4 months of lorlatinib (partial response), and at second relapse after 10.5 months of lorlatinib treatment. B, Allele frequency of HRAS p.Q61L in tumor tissue at different time points. C, Levels of ctDNA. D, Clinical tumor markers, values are normalized to the upper reference limit (URL) for each marker. CGA, chromogranin A; Lorla, lorlatinib; ND, not detected.
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