Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Non-KREEP origin for Chang'e-5 basalts in the Procellarum KREEP Terrane.

Mare volcanics on the Moon are the key record of thermo-chemical evolution throughout most of lunar history1-3. Young mare basalts-mainly distributed in a region rich in potassium, rare-earth elements and phosphorus (KREEP) in Oceanus Procellarum, called the Procellarum KREEP Terrane (PKT)4-were thought to be formed from KREEP-rich sources at depth5-7. However, this hypothesis has not been tested with young basalts from the PKT. Here we present a petrological and geochemical study of the basalt clasts from the PKT returned by the Chang'e-5 mission8. These two-billion-year-old basalts are the youngest lunar samples reported so far9. Bulk rock compositions have moderate titanium and high iron contents  with KREEP-like rare-earth-element and high thorium concentrations. However, strontium-neodymium isotopes indicate that these basalts were derived from a non-KREEP mantle source. To produce the high abundances of rare-earth elements and thorium, low-degree partial melting and extensive fractional crystallization are required. Our results indicate that the KREEP association may not be a prerequisite for young mare volcanism. Absolving the need to invoke heat-producing elements in their source implies a more sustained cooling history of the lunar interior to generate the Moon's youngest melts.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation.

BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study. METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety. RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug discontinuation in 6.9% of patients. CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; ClinicalTrials.gov number, NCT03785249.).

Dual functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation.

Gastrulation begins when the epiblast forms the primitive streak or becomes definitive ectoderm. During this lineage bifurcation, the DNA dioxygenase TET1 has bipartite functions in transcriptional activation and repression, but the mechanisms remain unclear. By converting mouse embryonic stem cells (ESCs) into neuroprogenitors, we defined how Tet1-/- cells switch from neuroectoderm fate to form mesoderm and endoderm. We identified the Wnt repressor Tcf7l1 as a TET1 target that suppresses Wnt/ß-catenin and Nodal signalling. ESCs expressing catalytic dead TET1 retain neural potential but activate Nodal and subsequently Wnt/ß-catenin pathways to generate also mesoderm and endoderm. At CpG-poor distal enhancers, TET1 maintains accessible chromatin at neuroectodermal loci independently of DNA demethylation. At CpG-rich promoters, DNA demethylation by TET1 affects the expression of bivalent genes. In ESCs, a non-catalytic TET1 cooperation with Polycomb represses primitive streak genes; post-lineage priming, the interaction becomes antagonistic at neuronal genes, when TET1's catalytic activity is further involved by repressing Wnt signalling. The convergence of repressive DNA and histone methylation does not inhibit neural induction in Tet1-deficient cells, but some DNA hypermethylated loci persist at genes with brain-specific functions. Our results reveal versatile switching of non-catalytic and catalytic TET1 activities based on genomic context, lineage and developmental stage.

Acquired Resistance to KRASG12C Inhibition in Cancer.

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).

Automated Generation of hiPSC-Derived Hepatic Progeny by Cost-Efficient Compounds.

Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) hold great promise for liver disease modeling, drug discovery, and drug toxicity screens. Yet, several hurdles still need to be overcome, including among others decrease in the cost of goods to generate HLCs and automation of the differentiation process. We here describe that the use of an automated liquid handling system results in highly reproducible HLC differentiation from hPSCs. This enabled us to screen 92 chemicals to replace expensive growth factors at each step of the differentiation protocol to reduce the cost of goods of the differentiation protocol by approximately 79%. In addition, we also evaluated several recombinant extracellular matrices to replace Matrigel. We demonstrated that differentiation of hPSCs on Laminin-521 using an optimized small molecule combination resulted in HLCs that were transcriptionally identical to HLCs generated using the growth factor combinations. In addition, the HLCs created using the optimized small molecule combination secreted similar amounts of albumin and urea, and relatively low concentrations of alfa-fetoprotein, displayed similar CYP3A4 functionality, and a similar drug toxicity susceptibility as HLCs generated with growth factor cocktails. The broad applicability of the new differentiation protocol was demonstrated for 4 different hPSC lines. This allowed the creation of a scalable, xeno-free, and cost-efficient hPSC-derived HLC culture, suitable for high throughput disease modeling and drug screenings, or even for the creation of HLCs for regenerative therapies.

Pan-tumor survey of ROS1 fusions detected by next-generation RNA and whole transcriptome sequencing.

BACKGROUND: Two ROS1 tyrosine kinase inhibitors have been approved for ROS1 fusion positive (ROS1+) non-small cell lung cancer (NSCLC) tumors. We performed a pan-tumor analysis of the incidence of ROS1 fusions to assess if more ROS1+ patients who could benefit from ROS1 TKIs could be identified. METHODS: A retrospective analysis of ROS1 positive solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ). RESULTS: A total of 259 ROS1+ solid malignancies were identified from approximately 175,350 tumors that underwent next-generation sequencing (12% from targeted RNA sequencing [Archer]; 88% from whole transcriptome sequencing). ROS1+ NSCLC constituted 78.8% of the ROS1+ solid malignancies, follow by glioblastoma (GBM) (6.9%), and breast cancer (2.7%). The frequency of ROS1 fusion was approximately 0.47% among NSCLC, 0.29% for GBM, 0.04% of breast cancer. The mean tumor mutation burden for all ROS1+ tumors was 4.8 mutations/megabase. The distribution of PD-L1 (22C3) expression among all ROS1+ malignancies were 0% (18.6%), 1%-49% (29.4%), and ≥ 50% (60.3%) [for NSCLC: 0% (17.8%); 1-49% (27.7%); ≥ 50% (53.9%). The most common genetic co-alterations of ROS1+ NSCLC were TP53 (29.1%), SETD2 (7.3%), ARIAD1A (6.3%), and U2AF1 (5.6%). CONCLUSIONS: ROS1+ NSCLC tumors constituted the majority of ROS1+ solid malignancies with four major fusion partners. Given that > 20% of ROS1+ solid tumors may benefit from ROS1 TKIs treatment, comprehensive genomic profiling should be performed on all solid tumors.

TRUST-II: a global phase II study of taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors.

Crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer. However, unmet needs remain, including treatment of patients with resistance mutations, efficacy in brain metastasis and avoidance of neurological side effects. Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address brain metastasis while conferring fewer neurological adverse events. All of these features are demonstrated and supported by the interim data from the regional phase II TRUST-I clinical study. Here we describe the rationale and design of TRUST-II, a global phase II study of taletrectinib in patients with locally advanced/metastatic ROS1+ non-small-cell lung cancer and other ROS1+ solid tumors. The primary end point is confirmed objective response rate. Secondary end points include duration of response, progression-free survival, overall survival and safety. This trial is enrolling patients in North America, Europe and Asia.

The targeted therapies crizotinib and entrectinib are the first options available to treat a type of lung cancer called ROS1 fusion-positive non-small-cell lung cancer (ROS1⁺ NSCLC). However, not all patients with ROS1⁺ NSCLC respond to these drugs. In addition, most patients who take these drugs find their cancer eventually develops resistance and begins to grow again. Patients with disease that has spread (metastasized) to the brain have worse outcomes. Taletrectinib is a new type of targeted therapy that is being developed to treat people who have metastatic ROS1⁺ NSCLC. Data from a regional phase II clinical trial showed that taletrectinib is well tolerated, effective for patients who have never taken a ROS1 targeted therapy and inhibits ROS1⁺ NSCLC for patients whose cancer has developed some types of resistance to these drugs. It has also been shown to treat ROS1⁺ NSCLC tumors that have spread to the brain. This article discusses the rationale and design of a new trial called TRUST-II, which is a global phase II clinical trial looking at how well taletrectinib works and how safe it is. TRUST-II is actively enrolling patients in North America, Europe and Asia. Clinical Trial Registration: NCT04919811 (ClinicalTrials.gov).

Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study.

BACKGROUND: ROS1-rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in ROS1-rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of ROS1-rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice. METHODS: Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n = 67) or crizotinib (n = 168). RESULTS: The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib (n = 168) had significantly longer median progression-free survival (PFS) than chemotherapy (n = 67) (18.0 months vs. 7.0 months, p < 0.001). Patients harboring single CD74-ROS1 (n = 90) had significantly shorter median PFS with crizotinib than those harboring non-CD74 ROS1 fusions (n = 69) (17.0 months vs. 21.0 months; p = 0.008). Patients with baseline brain metastasis (n = 45) had a significantly shorter PFS on first-line crizotinib than those without brain metastasis (n = 123) (16.0 months vs. 22.0 months; p = 0.03). At progression, intracranial-only progression (n = 40), with or without baseline CNS metastasis, was associated with longer median PFS than those with extracranial-only progression (n = 64) (19.0 months vs. 13.0 months, p < 0.001). TP53 mutations were the most common concomitant mutation, detected in 13.1% (7/54) of patients with CD74-ROS1 fusions, and 18.8% (6/32) with non-CD74 ROS1 fusions. Patients with concomitant TP53 mutations (n=13) had significantly shorter PFS than those who had wild-type TP53 (n = 81) (6.5 months vs. 21.0 months; p < 0.001). PFS was significantly shorter for the patients who harbored concomitant driver mutations (n = 9) (11.0 months vs 24.0 months; p = 0.0167) or concomitant tumor suppressor genes (i.e., TP53, RB1, or PTEN) (n = 25) (9.5 months vs 24.0 months; p < 0.001) as compared to patients without concomitant mutations (n = 58). CONCLUSION: Our results demonstrate that baseline brain metastatic status and various molecular factors could contribute to distinct clinical outcomes from first-line crizotinib therapy of patients with ROS1-rearranged lung cancer. CLINICAL TRIALS REGISTRATION: CORE, NCT03646994.

ALTA-2: Phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC). However, almost all patients eventually develop progressive disease on first-line ALK TKIs (e.g., crizotinib, alectinib and ceritinib). Brigatinib, a second-generation ALK TKI, may show efficacy in alectinib- and ceritinib-refractory ALK+ NSCLC. We describe the rationale and design of ALTA-2, a Phase II study of brigatinib in patients with locally advanced/metastatic ALK+ NSCLC and documented progressive disease on alectinib or ceritinib. The primary end point is confirmed objective response rate per independent review committee using response evaluation criteria in solid tumors version 1.1. Secondary end points include duration of response, progression-free survival, overall survival, safety and health-related quality of life.

Lay abstract Tyrosine kinase inhibitor medications (like crizotinib, alectinib or ceritinib) may work as the first treatment for people with non-small-cell lung cancer (NSCLC) that has spread to other parts of the body and has the ALK+ mutation (ALK+ NSCLC) in tumor testing. However, after a while, many people stop responding to treatment with one of these medicines. Brigatinib is a tyrosine kinase inhibitor medicine that may be effective in people with ALK+ NSCLC who have stopped responding to alectinib or ceritinib treatment. We describe the need for and design of a study of brigatinib in people with ALK+ NSCLC whose disease got worse on alectinib or ceritinib. Clinical trial registration: NCT03535740 (ClinicalTrials.gov).

Superabsorbent polymer balls as foreign bodies in the nasal cavities of children: our clinical experience.

OBJECTIVE: To summarize the clinical diagnosis and treatment of superabsorbent polymer balls as nasal foreign bodies in children. METHODS: We retrospectively analysed the clinical data concerning 12 cases of superabsorbent polymer balls as nasal foreign bodies in children and summarized the corresponding clinical features, methods of diagnoses and treatment, and prognoses. RESULTS: Twelve children with superabsorbent polymer balls as foreign bodies in their nasal cavities presented with relatively severe symptoms, such as congestion, runny nose, and nasal swelling. When such foreign bodies stay in the nasal cavity for a prolonged period, patients may suffer from general discomfort, such as agitation, poor appetite and high fever. Most of the children had to undergo nasal endoscopy under general anaesthesia to have the foreign bodies completely removed. An intraoperative examination revealed significant mucosal injury within the nasal cavity. With regular follow-up visits and adequate interventions, all the patients recovered. CONCLUSION: The longer superabsorbent polymer balls remain in the nasal cavity, the more damaged the nasal mucosa will be. It is challenging to remove such foreign bodies in the outpatient setting. Transnasal endoscopy under general anaesthesia appears to be safer and more effective in such cases. Since the nasal mucosa is injured to varying degrees, postoperative follow-up and treatment are equally important for preventing the occurrence of complications.

A first-aid fast track channel for rescuing critically ill children with airway foreign bodies: our clinical experience.

OBJECTIVE: To explore the role of a first-aid fast track channel in rescuing children with airway foreign bodies and to analyse and summarize the experience and lessons of the first-aid fast track channel in rescuing airway foreign bodies from patients in critical condition. METHODS: We retrospectively reviewed the medical records of children with airway foreign bodies rescued by first-aid fast track channels admitted to our hospital from January 2017 to December 2020. The corresponding clinical features, treatments, and prognoses were summarized. RESULTS: Clinical data from 21 cases of first-aid fast track channel patients were retrospectively collected, including 12 males and 9 females aged 9-18 months. Cough was the most frequently exhibited symptom (100.0%), followed by III inspiratory dyspnoea (71.4%). Regarding the location of foreign bodies, 5 cases (23.8%) had glottic foreign bodies, 10 cases (47.6%) had tracheal foreign bodies, and 6 cases (28.6%) had bilateral bronchial foreign bodies. The most common type of FB was organic. FB removal was performed by rigid bronchoscopy in every case, and there were no complications of laryngeal oedema, subcutaneous emphysema, or pneumothorax. No tracheotomy was performed in any of the children. CONCLUSION: The first-aid fast track channel for airway foreign bodies saves a valuable time for rescue, highlights the purpose of rescue, improves the success rate of rescue and the quality of life of children, and is of great value for the treatment of critical tracheal foreign bodies. It is necessary to regularly summarize the experience of the first-aid fast track channel of airway foreign bodies and further optimize the setting of the first-aid fast track channel.

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.

PURPOSE: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. EXPERIMENTAL DESIGN: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. RESULTS: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. CONCLUSION: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. IMPLICATIONS FOR PRACTICE: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.

Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODS: In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTS: During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONS: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).

Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial.

BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most known resistance mutations in ALK and ROS1. We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive non-small-cell lung cancer (NSCLC). METHODS: In this open-label, single-arm, phase 1-2 trial, we enrolled patients (aged ≥18 years) with histologically or cytologically confirmed advanced ROS1-positive NSCLC, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 2 or less (≤1 for phase 1 only) from 28 hospitals in 12 countries worldwide. Lorlatinib 100 mg once daily (escalating doses of 10 mg once daily to 100 mg twice daily in phase 1 only) was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was overall and intracranial tumour response, assessed by independent central review. Activity endpoints were assessed in patients who received at least one dose of lorlatinib. This study is ongoing and is registered with ClinicalTrials.gov, NCT01970865. FINDINGS: Between Jan 22, 2014, and Oct 2, 2016, we assessed 364 patients, of whom 69 with ROS1-positive NSCLC were enrolled. 21 (30%) of 69 patients were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. The estimated median duration of follow-up for response was 21·1 months (IQR 15·2-30·3). 13 (62%; 95% CI 38-82) of 21 TKI-naive patients and 14 (35%; 21-52) of 40 patients previously treated with crizotinib as their only TKI had an objective response. Intracranial responses were achieved in seven (64%; 95% CI 31-89) of 11 TKI-naive patients and 12 (50%; 29-71) of 24 previous crizotinib-only patients. The most common grade 3-4 treatment-related adverse events were hypertriglyceridaemia (13 [19%] of 69 patients) and hypercholesterolaemia (ten [14%]). Serious treatment-related adverse events occurred in five (7%) of 69 patients. No treatment-related deaths were reported. INTERPRETATION: Lorlatinib showed clinical activity in patients with advanced ROS1-positive NSCLC, including those with CNS metastases and those previously treated with crizotinib. Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent. FUNDING: Pfizer.

Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.

BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. METHODS: In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. FUNDING: Pfizer.

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC.

BACKGROUND: We evaluated the cumulative incidence rate (CIR) of central nervous system (CNS) and non-CNS progression in alectinib-treated patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to determine the extent to which alectinib may treat or control CNS disease. METHODS: Patients with crizotinib-pretreated locally advanced or metastatic disease received alectinib 600 mg orally twice daily in two phase II trials. All patients underwent baseline imaging and regular centrally reviewed scans. RESULTS: At 24 months, the CIR for CNS progression was lower in patients without vs with baseline CNS metastases (8.0 vs 43.9%). Patients with baseline CNS disease and prior radiotherapy had a higher CIR of CNS progression than radiotherapy-naive patients (50.5 vs 27.4%) and a lower CIR of non-CNS progression (25.8 vs 42.5%). Adverse events leading to withdrawal occurred in 5.9% and 6.7% of patients with and without baseline CNS metastases, respectively. CONCLUSIONS: This analysis indicates a potential role for alectinib in controlling and preventing CNS metastases.

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing.

BACKGROUND: In our recent study, of cases positive for epidermal growth factor receptor (EGFR) exon 19 deletions using comprehensive genomic profiling (CGP), 17/77 (22%) patients with prior standard of care (SOC) EGFR testing results available were previously negative for exon 19 deletion. Our aim was to compare the detection rates of CGP versus SOC testing for well-characterized sensitizing EGFR point mutations (pm) in our 6,832-patient cohort. MATERIALS AND METHODS: DNA was extracted from 40 microns of formalin-fixed paraffin-embedded sections from 6,832 consecutive cases of non-small cell lung cancer (NSCLC) of various histologies (2012-2015). CGP was performed using a hybrid capture, adaptor ligation-based next-generation sequencing assay to a mean coverage depth of 576×. Genomic alterations (pm, small indels, copy number changes and rearrangements) involving EGFR were recorded for each case and compared with prior testing results if available. RESULTS: Overall, there were 482 instances of EGFR exon 21 L858R (359) and L861Q (20), exon 18 G719X (73) and exon 20 S768I (30) pm, of which 103 unique cases had prior EGFR testing results that were available for review. Of these 103 cases, CGP identified 22 patients (21%) with sensitizing EGFR pm that were not detected by SOC testing, including 9/75 (12%) patients with L858R, 4/7 (57%) patients with L861Q, 8/20 (40%) patients with G719X, and 4/7 (57%) patients with S768I pm (some patients had multiple EGFR pm). In cases with available clinical data, benefit from small molecule inhibitor therapy was observed. CONCLUSION: CGP, even when applied to low tumor purity clinical-grade specimens, can detect well-known EGFR pm in NSCLC patients that would otherwise not be detected by SOC testing. Taken together with EGFR exon 19 deletions, over 20% of patients who are positive for EGFR-activating mutations using CGP are previously negative by SOC EGFR mutation testing, suggesting that thousands of such patients per year in the U.S. alone could experience improved clinical outcomes when hybrid capture-based CGP is used to inform therapeutic decisions. IMPLICATIONS FOR PRACTICE: This study points out that genomic profiling, as based on hybrid capture next-generation sequencing, can identify lung cancer patients with point mutation in epidermal growth factor receptor (EGFR) missed by standard molecular testing who can likely benefit from anti-EGFR targeted therapy. Beyond the specific findings regarding false-negative point mutation testing for EGFR, this study highlights the need for oncologists and pathologists to be cognizant of the performance characteristics of testing deployed and the importance of clinical intuition in questioning the results of laboratory testing.

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers.

BACKGROUND: Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. MATERIALS AND METHODS: We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. RESULTS: A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. CONCLUSIONS: Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. The Oncologist 2017;22:152-157Implications for Practice: Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.