ALK amplification

P1, N=65, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1b, N=44, Terminated, Pfizer | Active, not recruiting --> Terminated; Termination of further treatment on the study due to the availability of commercial supply or a rollover study (NCT05160922) that will allow active subjects to continue receiving treatment.

Although the sample size of patients receiving targeted therapies was limited, the study highlighted improved overall survival and progression-free survival rates compared to earlier trials, suggesting advancements in systemic lung metastasis treatment. The study suggests that as more targeted therapies emerge, the prospects for increased overall survival and progression-free survival in lung brain metastasis patients will likely improve.

MET-amplified, ALK + NSCLC often presents with high-level and heterogeneous amplification in tissue, seldom overlaps with ALK mutations, and frequently co-occurs with alterations associated with aggressive tumor biology.

Conclusions The combination of GGTT and osimertinib improves TTF and OS in EGFR mutation positive NSCLC patients failing osimertinib. Future prospective comparative study is warranted.

HGSOC harbouring activating ALK mutations might be associated with a better survival, while ALK overexpression and ALK amplification does not impact the prognosis.

In Cohort 1 (n=21), 15 (71%) pts had progressed on alectinib, 5 (24%) on ceritinib and 1 (5%) on ensartinib. In Cohort 2 (n=18), pts had progressed on crizotinib followed by alectinib (n=9, 50%), ceritinib (n=4, 22%) or brigatinib (n=3, 17%); 2 (11%) pts progressed on crizotinib, then ceritinib followed by alectinib...Of 5 pts with ALK resistance mutations (I1171N, V1180L, L1196M, G1202R, and E1210K) who subsequently received lorlatinib, repeat ctDNA NGS after 2 months demonstrated clearance of ALK resistance mutation(s) in 4/5 (80%) pts (i.e. undetectable on repeat testing)... Resistance mechanisms to ALK inhibitors are heterogenous, including both ALK dependent and independent pathways. DDR and cell cycle gene alterations were commonly detected and may represent previously unreported acquired resistance alterations. Comprehensive ctDNA NGS analysis at progression may help detect novel resistance alterations in patients on ALK inhibitors.

P1b, N=44, Active, not recruiting, Pfizer | Trial completion date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2023 --> Jul 2023

P1, N=65, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Recruiting --> Active, not recruiting

The considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.

In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

These findings support expanded evaluation of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs.

These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs.

These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target.

P1b, N=44, Active, not recruiting, Pfizer | Trial completion date: Dec 2022 --> Apr 2023 | Trial primary completion date: Dec 2022 --> Apr 2023

P=N/A, N=0, Withdrawn, University of Colorado, Denver | N=40 --> 0 | Trial completion date: Apr 2025 --> Sep 2022 | Recruiting --> Withdrawn | Trial primary completion date: Apr 2024 --> Sep 2022

Of these, 52 received first-line alectinib treatment (1L) and 56 received alectinib after crizotinib resistance (2L). Also, NF2-mutant patients only had a median PFS of 4 months, significantly poorer than those without (HR 11.1, 95CI 2.17-50; p<0.001). Conclusions By analyzing different mutational profiles of ALK-rearranged patients after alectinib treatment, we proposed MET and NF2 as putative mechanisms that conferred resistance to early resistance of first-line alectinib, which shone light on future tailored treatment for ALK-positive NSCLCs.

Targeted ALK inhibitor agents, such as crizotinib, have been effective in the relapse setting and are currently being evaluated in combination with backbone multimodal therapy in the upfront setting for high-risk ALK+ neuroblastoma... While familial neuroblastoma is rare, early detection of germline ALK mutations in patients and survivors can have a major impact on family planning and cancer surveillance in offspring. Survivors with autosomal dominant ALK mutations, like our patients mother, carry a 50% chance of passing the mutation on to each child who then carries a 5060% chance of developing a neuroblastoma-spectrum tumor if inherited. Germline ALK testing should be strongly considered in survivors of ALK+ and ALK-unknown neuroblastoma.

While ATC carrying BRAF mutations can benefit from BRAF-inhibitors and this effect might be enhanced by a combined strategy including PIK3CA-inhibitors in some of the patients, alterations in BRAF wild-type ATC are not directly targeted by currently FDA approved options.

ADCs directed to ALK-expressing cancers are a promising therapeutic approach. The efficacy of the ADCs are currently being tested in NBL and FP RMS mouse models, and will be reported.

In the era of comprehensive genomic profiling, several resistance alterations with extremely low prevalence may be detected, especially in CRCs that do not bear other genomic drivers. Negative ultra-selection may represent a relevant step forward in precision medicine in patients with RAS/BRAF wt MSS mCRC potentially eligible for EGFR blockade.

One patient had acquired EGFR T790M, STRN-ALK fusion, and EGFR amplification after gefitinib progression and was shortly resistant to osimertinib with MET amplification. The other patient developed to acquired EGFR T790M and MET amplification post-dacomitinib and acquired CCDC6-RET fusion after 4-month osimertinib treatment...The T790M accompanying diver gene resistance will be a new subtype after EGFR-TKIs progression and needs effective treatment options. Legal entity responsible for the study The authors.

P1, N=40, Recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2022

P=N/A, N=40, Recruiting, University of Colorado, Denver | Not yet recruiting --> Recruiting

There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.

P=N/A, N=40, Not yet recruiting, University of Colorado, Denver

P1/2, N=50, Recruiting, Memorial Sloan Kettering Cancer Center

Mutations in RAD54L (P=0.018) and MYC (P=0.04) were more common in FP patients; HPD patients showed more frequent RAD54L mutations (P<0.001). We demonstrated different genomic characteristics across different progression patterns following ICI treatment, which might assist clinicians in the prediction of a patient's response, identifying candidates for more effective ICI therapy.

Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

High protein expression of both ALK-1 and h-TERT, as well as ALK-A had a poor impact on the prognosis of GBM. Further studies are needed to establish the underlying mechanisms.

Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.

P1, N=40, Recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Dec 2020 --> Dec 2022 | Trial primary completion date: May 2020 --> Dec 2021

An ALK IHC "equivocal" interpretation category should be incorporated into practice. Atypical patterns of ROS1 and genomic heterogeneity need to be evaluated further for any clinical relevance.

We demonstrated that IHC positive test, in these cases, must be interpreted with caution. FISH analysis has to be recommended to confirm IHC results in case of unusual phenotype, such as smoker or lung cancer other than adenocarcinoma. Although lung carcinoma with ALK rearrangement seems to be not sensitive to ICI, further investigations should be conducted on other types of ALK molecular alterations. ALK amplifications, as observed in the present case, should not be an impediment to taking into account the PD-L1 marking for the initiation of treatment by immunotherapy.

Copy number analyses of genes between PPP1CB and ALK using RT-qPCR suggest that the PPP1CB-ALK is likely the result of local chromothripsis followed by episomal amplification. Transcriptome sequencing demonstrated high-level SOX2 expression and predicted WNT/β-catenin pathway activation, suggesting possible therapeutic approaches.

Conclusion Alectinib efficacy and safety profile in this study align with known alectinib results in post-crizotinib setting. Identification of mechanisms of resistance emerging from exposure to previous ALK inhibitor was feasible and helped selecting subsequent treatment options.

P1b, N=44, Active, not recruiting, Pfizer | Trial completion date: Dec 2020 --> Dec 2022 | Trial primary completion date: Dec 2020 --> Dec 2022

The combination of a genetic analysis and computational simulation model may make a prediction of resistance mechanisms for overcoming ALK-TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

Our preliminary study shows that ALK+-adenocarcinomas should be evaluated in the context of their genomic background in order to better understand and predict patients´ individual course of disease.