FDA Approves Companion Diagnostic for Lorlatinib in ALK-Positive Lung Cancer


The FDA has approved the VENTANA ALK CDx assay as a companion diagnostic to identify patients with ALK-positive non–small cell lung cancer who are eligible to receive treatment with lorlatinib.

The FDA has approved the VENTANA ALK (D5F3) CDx assay as a companion diagnostic to identify patients with ALK-positive non–small cell lung cancer (NSCLC) who are eligible to receive treatment with lorlatinib (Lorbrena).1

On March 3, 2021, the FDA gave the green light to expand the indication of lorlatinib to include use in the frontline treatment of patients with ALK-positive NSCLC based on data from the phase 3 CROWN trial (NCT03052608), where the agent led to a 72% reduction in the risk of progression or death vs crizotinib (Xalkori) in treatment-naïve patients (HR, 0.28; 95% CI, 0.19-0.41; P <.0001) per blinded independent central review assessment.2

Previously, in November 2018, the regulatory agency granted an accelerated approval to lorlatinib for use in patients with ALK-positive NSCLCwhose disease had progressed on crizotinib and at least 1 other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor treatment for metastatic disease. The decision was based on a subgroup of 215 patients with ALK-positive metastatic NSCLC from Study B7461001 (NCT01970865), in which lorlatinib elicited an overall response rate of 48% (95% CI, 42%-55%).3

“The FDA approval is great news for [patients with] ALK-positive [NSCLC],” Jill German, head of Roche Pathology Customer Segment, stated in a press release. “It is essential that we identify patients with this cancer biomarker quickly and accurately so they can be treated with effective targeted therapy. This label expansion advances Roche’s commitment to personalized healthcare by providing [patients with] lung cancer with access to more treatment options and a better chance for progression-free survival compared to standard of care.”

The VENTANA ALK (D5F3) CDx assay was developed to qualitatively identify the ALK protein in formalin-fixed, paraffin-embedded NSCLC tissue stained with a BenchMark ULTRA or BenchMark XT automated staining instrument.

The assay is now approved for use as a companion diagnostic for the following 4 targeted therapies: crizotinib, ceritinib (Zykadia), alectinib (Alecensa), and lorlatinib. Data from previous studies have demonstrated that the assay is able to identify more patients with NSCLC who may derive benefit from an ALK-targeted treatment compared with fluorescent in situ hybridization (FISH) testing.

In 1 study, investigators selected patients with stage IV NSCLC who received crizotinib. Investigators assessed their tumors to detect ALK rearrangements through the use of either FISH or the VENTANA ALK (D5F3) CDx assay.4

Twenty-nine patients with advanced, ALK-positive NSCLC diagnosed by FISH or the VENTANA assay on either small biopsies or fine-needle aspirations were given ALK inhibitors. All patients determined to have ALK aberrations via the VENTANA assay responded to crizotinib with the exception of 3 patients who had primary resistance. No response was observed in 13 patients who tested positive for ALK aberrations via FISH but were negative via the VENTANA assay; this was confirmed using an external cohort of 16 patients.

In another study, investigators evaluated the potential of combining immunohistochemistry (IHC) via the VENTANA assay and FISH to determine the affordability of the approach. Investigators evaluated 410 unselected lung adenocarcinomas through the use of both tests.5

Cases were examined as IHC score 3+ (n = 26), score 2+ (n = 9), score 1+ (n = 51), and score 0 (n = 282). Twenty-three of the 26 IHC 3+ and 5 of the 9 IHC 2+ cases were FISH positive, whereas 3 of 26 IHC 3+, 4 of 9 IHC 2+, and all 333 IHC 1+/0 cases were FISH negative. If FISH was considered to be the standard approach, then the sensitivity and specificity of the VENTANA assay for 3+/2+ as ALK positive were 100% and 97.9%, respectively. Notably, 2 of the IHC 3+ cases that were reported to be negative via FISH, were actually positive for ALK aberrations.

On the final classify, the sensitivity and specificity for ALK IHC 3+/2+ was 100% and 98.8%, respectively; FISH was 90.3% sensitive and 100% specific. The investigators concluded that the VENTANA assay was able to detect some ALK-positive cases that might have been missed by FISH.

In another study, investigators conducted FISH and IHC analyses on 297 lung adenocarcinomas. The VENTANA assay and the real-time polymerase chain reaction (qRT-PCR) assay were applied to evaluate the ALK mutational status in the discordant cases of FISH and IHC.6

Results indicated that there was 100% sensitivity with IHC, with a specificity of 81.8% for detecting ALK-positive cases. Eight ALK-expressed cases were negative, 5 of which had the ALK aberration detected via qRT-PCR. Three of those 5 cases showed ALK expression per the VENTANA assay.


  1. Roche receives FDA approval for VENTANA ALK (D5F3) CDx assay to identify lung cancer patients eligible for targeted treatment with LORBRENA (lorlatinib). News release. Roche. March 9, 2021. Accessed March 9, 2021. http://prn.to/3ry878u
  2. US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. March 3, 2021. Accessed March 9, 2021. http://bit.ly/30e9cWU
  3. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. News release. FDA. November 2, 2018. Accessed March 9, 2021. http://bit.ly/3sY5jBO
  4. van der Wekken AJ, Pelgrim R, Hart N’t, et al. Dichotomous ALK-IHC is a better predictor for ALK inhibition outcome than traditional ALK-FISH in advanced non–small cell lung cancer. Clin Cancer Res. 2017;233(15):4251-4258. doi:10.1158/1078-0432.CCR-16-1631
  5. Zhou J, Zhao J, Sun K, et al. Accurate and economical detection of ALK positive lung adenocarcinoma with semiquantitative immunohistochemical screening. PLoS One. 2014;9(3):e92828. doi:10.1371/journal.pone.0092828
  6. Shan L, Lian F, Guo L, et al. Combination of conventional immunohistochemistry and qRT-PCR to detect ALK rearrangement. Diagn Pathol. 2014;9:3. doi:10.1186/1746-1596-9-3

This article was originally published on OncLive as, "FDA Approves Companion Diagnostic for Lorlatinib in ALK+ NSCLC."

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