TEST:

Guardant360® CDx

On January 27, 2023, the Food and Drug Administration (FDA) approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with elacestrant.

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of:...adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.

LUMAKRAS is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

RYBREVANT is a bispecific EGF receptor-directed and MET receptordirected antibody indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, ] whose disease has progressed on or after platinum-based chemotherapy.

For patients with advanced NSCLC and an activating HER2 (ERBB2) mutation, as detected by an US Food and Drug Administration–approved test, and who have received prior systemic therapy, clinicians may offer treatment (monotherapy) with trastuzumab deruxtecan...

Based on ctDNA, ORRs were generally higher in the lorlatinib vs crizotinib arm, reaching 80% and 72% for EML4-ALK v1 and v3, respectively, in the lorlatinib arm, and 50% and 74% in the crizotinib arm....Pts with untreated ALK+ advanced NSCLC had higher ORRs and potentially longer PFS across predefined biomarker subgroups when treated with lorlatinib compared with crizotinib in the phase 3 CROWN study.

Based on ctDNA, ORRs were generally higher in the lorlatinib vs crizotinib arm, reaching 80% and 72% for EML4-ALK v1 and v3, respectively, in the lorlatinib arm, and 50% and 74% in the crizotinib arm....Pts with untreated ALK+ advanced NSCLC had higher ORRs and potentially longer PFS across predefined biomarker subgroups when treated with lorlatinib compared with crizotinib in the phase 3 CROWN study.

Pts with co-occurring EML4-ALK V3 and TP53 mutation had the shortest TTD (median TTD 8.7 [3.9–NR; HR: 2.59; P=0.0219]; Table).

POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in the United States and Canada....Patients in the biomarker analysis group provided consent for serial blood sample collection, received ≥1 dose of initial palbociclib combination treatment...Patients with mutated ESR1 and PIK3CA or CCND1 and FGFR1 amp at baseline had shorter rwPFS than patients with wild-type genes .

POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in the United States and Canada....Patients in the biomarker analysis group provided consent for serial blood sample collection, received ≥1 dose of initial palbociclib combination treatment...Patients with mutated ESR1 and PIK3CA or CCND1 and FGFR1 amp at baseline had shorter rwPFS than patients with wild-type genes .

POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in the United States and Canada....Patients in the biomarker analysis group provided consent for serial blood sample collection, received ≥1 dose of initial palbociclib combination treatment...Patients with mutated ESR1 and PIK3CA or CCND1 and FGFR1 amp at baseline had shorter rwPFS than patients with wild-type genes .

CONTRADICTING EVIDENCE: POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in the United States and Canada....Patients in the biomarker analysis group provided consent for serial blood sample collection, received ≥1 dose of initial palbociclib combination treatment...Patients with mutated ESR1 and PIK3CA or CCND1 and FGFR1 amp at baseline had shorter rwPFS than patients with wild-type genes .

This retrospective study analyzed a cohort of Hispanic patients (N=103) diagnosed with mNSCLC from the US and seven Latin American countries (LATAM) treated with immune checkpoint inhibitors (ICI) alone or in combination...TMB-H favored better OS.

Transient transfection demonstrated that single mutations D538G, E380Q, F404L and wild-type ESR1 were sensitive to fulvestrant (p < 0.0001, p = 0.0006, p = 0.04 and p = 0.0001), whereas compound mutations D538G_F404L and E380Q_F404L were resistant.

Transient transfection demonstrated that single mutations D538G, E380Q, F404L and wild-type ESR1 were sensitive to fulvestrant (p < 0.0001, p = 0.0006, p = 0.04 and p = 0.0001), whereas compound mutations D538G_F404L and E380Q_F404L were resistant.

Transient transfection demonstrated that single mutations D538G, E380Q, F404L and wild-type ESR1 were sensitive to fulvestrant (p < 0.0001, p = 0.0006, p = 0.04 and p = 0.0001), whereas compound mutations D538G_F404L and E380Q_F404L were resistant.

Transient transfection demonstrated that single mutations D538G, E380Q, F404L and wild-type ESR1 were sensitive to fulvestrant (p < 0.0001, p = 0.0006, p = 0.04 and p = 0.0001), whereas compound mutations D538G_F404L and E380Q_F404L were resistant.

Overall, objective response rate (ORR) was 41.7% (95% CI: 22.1, 63.4)….Tepotinib showed meaningful activity, especially in first line, in the first trial of a MET inhibitor in EGFR WT NSCLC with high-level METamp to enroll based on a convenient LBx assay.

ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne)….In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC.

Transient transfection demonstrated that single mutations D538G, E380Q, F404L and wild-type ESR1 were sensitive to fulvestrant (p < 0.0001, p = 0.0006, p = 0.04 and p = 0.0001), whereas compound mutations D538G_F404L and E380Q_F404L were resistant.

ctDNA datawere available for 14 evaluable pts; 13 in which somatic alterations were detected. ctDNA analysis detected NTRK gene fusions in 46% of the pts at treatment start. Bythe data cut-off, 6 pts had a progression event with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts: one with NTRK1 F589L and G595R, one with SMAD4 R361C and the third with ARID1A K1238fs and FGFR2 R210Q mutations.

ctDNA datawere available for 14 evaluable pts; 13 in which somatic alterations were detected. ctDNA analysis detected NTRK gene fusions in 46% of the pts at treatment start. Bythe data cut-off, 6 pts had a progression event with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts: one with NTRK1 F589L and G595R, one with SMAD4 R361C and the third with ARID1A K1238fs and FGFR2 R210Q mutations.

ctDNA datawere available for 14 evaluable pts; 13 in which somatic alterations were detected. ctDNA analysis detected NTRK gene fusions in 46% of the pts at treatment start. Bythe data cut-off, 6 pts had a progression event with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts: one with NTRK1 F589L and G595R, one with SMAD4 R361C and the third with ARID1A K1238fs and FGFR2 R210Q mutations.

ctDNA datawere available for 14 evaluable pts; 13 in which somatic alterations were detected. ctDNA analysis detected NTRK gene fusions in 46% of the pts at treatment start. Bythe data cut-off, 6 pts had a progression event with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts: one with NTRK1 F589L and G595R, one with SMAD4 R361C and the third with ARID1A K1238fs and FGFR2 R210Q mutations.

ctDNA datawere available for 14 evaluable pts; 13 in which somatic alterations were detected. ctDNA analysis detected NTRK gene fusions in 46% of the pts at treatment start. Bythe data cut-off, 6 pts had a progression event with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts: one with NTRK1 F589L and G595R, one with SMAD4 R361C and the third with ARID1A K1238fs and FGFR2 R210Q mutations.

23 patients with tumor tissue confirmed NSCLC harboring HER2 exon 20 insertion mutations were studied….15 of the 16 (94%) patients demonstrated a decrease in mVAF at C3D1 compared to the mVAF at baseline. 12 of 15 patients demonstrated an >50% reduction in mVAF at C3D1, with 7 of the 12 patients showing >95% reduction in mVAF at C3D1 with clinical outcomes of 5 PRs, 1 non-CR/non-PD and 1 SD....Baseline plasma ctDNA genotyping correlated with tumor tissue based NGS in an NSCLC patient population with HER2 mutations. Poziotinib treatment resulted in mVAF reduction, which correlated with clinical response per RECIST1.1.

Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti-programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months.

...EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab...The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months...Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

Objective response rate (ORR) by IRC was 42% (10/24 pts) overall, 71% (5/7 pts) in 1L, 30% (3/10 pts) in 2L and 29% (2/7 pts) in 3L….In the first study of a MET inhibitor in NSCLC with METamp prospectively detected by liquid biopsy, tepotinib showed high and clinically meaningful activity, especially in 1L, and was generally well tolerated.

A total of 15 eligible patients received osimertinib. Before starting treatment, EGFR-activating mutations were detected in the ctDNA of all patients, and EGFR T790M was detected in 93% of the cases. Osimertinib treatment was associated with an objective response rate of 53% and a median progression-free survival of 7.3 months. A total of 12 of the 15 patients had undetectable plasma T790M and decreased activating mutation allelic frequency (AF) at week 4. None of the 12 patients had disease progression within 16 weeks.

A total of 15 eligible patients received osimertinib. Before starting treatment, EGFR-activating mutations were detected in the ctDNA of all patients, and EGFR T790M was detected in 93% of the cases. Osimertinib treatment was associated with an objective response rate of 53% and a median progression-free survival of 7.3 months. 

Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer...cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant)...18 (60%) of 30 patients with an AKT1 mutation in ctDNA and oestrogen receptor-positive cancer were enrolled in cohort C...All 18 patients were evaluable; four (22% [95% CI 6–48]) patients had a confirmed partial response, and an additional four patients had unconfirmed partial responses...

In the subgroup of patients with hormone receptor-positive HER2-negative breast cancer treated with neratinib and fulvestrant, four (24% [95% CI 7–50]) of 17 patients had a confirmed response…

Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer...cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg)...Two (33%, 95% CI 4–78) of the six patients with AKT1 mutations responded, and there were two further unconfirmed responses in these patients.

The G1202R/Del mutation was detected in 23 pts samples; of which, 15 (65.2%) also harbored EML4-ALK variant 3. ORR was 33.3% (95% CI 16.5-54.0), 75.0% (95% CI 19.4-99.4) and 45.8% (95% CI 25.6-67.2) for variants 1, 2 and 3, respectively, while median DOR was similar for pts with variant 1 or 3 (both 6.9 months)...In this heavily pretreated group of ALK+ NSCLC pts, the presence of an ALK resistance mutation might enrich for EML4-ALK variants 1 and 3. Lorlatinib exhibited antitumor activity irrespective of EML4-ALK variant and across a variety of ALK resistance mutations.

Both ctDNA ERBB2 amp and PD-L1 positivity predicted response (24% vs. 0% [p = .0655] and 36% vs. 5% [p = .0367], respectively). In ctDNA ERBB2+/PD-L1+ pts, which were all GC, the ORR was 57% and DCR 86%....Our results suggest that M+P has encouraging preliminary activity in patients with advanced GC, and that biomarker selection based on ctDNA ERBB2 and PD-L1 could enrich for the responding population.

HER2+ (pre-T testing) PD-L1-unselected GEA pts were enrolled….Of 57 evaluable pts to date in expansion (30 NA and 27 A), best ORR was 16% and disease control rate (DCR) was 54%. Both ctDNA ERBB2 amp and PD-L1 positivity predicted response (24% vs. 0% [p = .0655] and 36% vs. 5% [p = .0367], respectively)....M+P is a well-tolerated regimen with antitumor activity in 2nd line HER2+ GEA.

Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months.

We present a patient with metastatic NSCLC harboring a compound EGFR mutation with co-occurring G719A and T790M mutation….Subsequent administration of afatinib led to a clinical and radiological response.

A 67-year-old male presented with stage IVB squamous cell carcinoma of lung with osseous metastases….Tissue next generation sequencing (NGS) showed EGFR G719A….Amivantamab monotherapy was initiated...Repeat scans in 6 weeks showed decreased leptomeningeal enhancement, and reduction in the size of parenchymal lesions, lung mass, and lymphadenopathies....Amivantamab monotherapy has shown an encouraging outcome in a patient with an atypical EGFR mutated (G719X) NSCLC with leptomeningeal disease who progressed on osimertinib.

A 71-year-old never-smoker Caucasian man...A biopsy from the lung mass revealed poorly differentiated adenocarcinoma of lung primary...Immunohistochemistry (IHC) for PD-L1...demonstrated tumor proportion score of 100%... Next generation sequencing...revealed KIF5B-RET fusion (4.9% of DNA)...In addition, concurrent TP53 (13.4%) and AR (0.2%) mutations were reported. FISH confirmed RET rearrangement...pembrolizumab...was initiated....Follow-up MRI and CT scan at 6 months after treatment showed a complete response...

Liquid biopsy test reported actionable alterations in ARID1A gene...Nivolumab 3 mg/kg intravenously every 2 weeks was administered for 38 cycles....The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation.

Liquid biopsy test reported actionable alterations in ARID1A gene...Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation....In December 2018, a PR was achieved with cisplatin plus pemetrexed reintroduction since October 2018 (Fig. 1), but the disease progressed shortly after. Immunotherapy rechallenge and vinorelbine did not succeed either.

Liquid biopsy test reported actionable alterations in ARID1A gene...The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation.

She received palliative radiation followed by 6 cycles of pembrolizumab by her then treating oncologist owing to a programmed death-ligand 1 (22C3) expression level of 90%. Initial plasma genotyping using Guardant360 (Guardant Health Inc., Redwood City, CA) around the time of diagnosis revealed KIF5B-RET fusion (allele frequency [AF]: 0.3%) and TP53 P190T (AF: 1.8%). Subsequent tumor genotyping revealed KIF5B-RET (K15, R12; AF: 16.10%) and TP53 P190T (AF: 51.05%) through FoundationOne CDx (Foundation Medicine Inc., Cambridge, MA)...The patient did not respond to 6 cycles of single-agent pembrolizumab...

She received palliative radiation followed by 6 cycles of pembrolizumab by her then treating oncologist owing to a programmed death-ligand 1 (22C3) expression level of 90%. Initial plasma genotyping using Guardant360 (Guardant Health Inc., Redwood City, CA) around the time of diagnosis revealed KIF5B-RET fusion (allele frequency [AF]: 0.3%) and TP53 P190T (AF: 1.8%). Subsequent tumor genotyping revealed KIF5B-RET (K15, R12; AF: 16.10%) and TP53 P190T (AF: 51.05%) through FoundationOne CDx (Foundation Medicine Inc., Cambridge, MA)...The patient did not respond to 6 cycles of single-agent pembrolizumab...

She received palliative radiation followed by 6 cycles of pembrolizumab by her then treating oncologist owing to a programmed death-ligand 1 (22C3) expression level of 90%. Initial plasma genotyping using Guardant360 (Guardant Health Inc., Redwood City, CA) around the time of diagnosis revealed KIF5B-RET fusion (allele frequency [AF]: 0.3%) and TP53 P190T (AF: 1.8%). Subsequent tumor genotyping revealed KIF5B-RET (K15, R12; AF: 16.10%) and TP53 P190T (AF: 51.05%) through FoundationOne CDx (Foundation Medicine Inc., Cambridge, MA)...The patient did not respond to 6 cycles of single-agent pembrolizumab...

A 71-year-old female presented in December 2017 after diagnosis of metastatic CCA….Guardant360 testing showed ERBB2 (HER2) amplification 3+...we began off-label treatment with anti-HER2 pertuzumab/trastuzumab combination therapy….After just one treatment, the patient’s liver function tests improved...Scans also showed excellent ongoing durable response...

A 71-year-old female presented in December 2017 after diagnosis of metastatic CCA….Guardant360 testing showed ERBB2 (HER2) amplification 3+ and was confirmed through tumor tissue-based immunohistochemistry...She was started on a combination carboplatin and gemcitabine...the patient had rapid progression of disease with rising tumor markers…

Retrospective analysis of the MEK2 mutations in serial plasma samples collected through the patient’s treatment course revealed emergence of these mutant alelles in concert with increases in fractional abundance of mutant BRAF and TP53 alleles (Figure 5E). Thus, these data likely reflect the emergence of heterogeneous polyclonal resistance mechanisms that evolved under the selective pressure of trametinib therapy.

...a second liquid biopsy was carried out, demonstrating a molecular response to the treatment with a spectacular decrease of molecular tumor burden, with FGFR1 amplification undetectable in plasma cfDNA (Fig 2), as well as MYC and RAF1 amplifications...Pazopanib was maintained at the same dose because of clinical benefit, sustained radiographic response, and undetectability of FGFR amplification in serial liquid biopsies.

We report 2 patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior treatment with multiple lines of therapy and underwent ctDNA testing, which detected MSI-H status. Both patients were treated with pembrolizumab, resulting in an excellent clinical response measured with liquid biopsies before and after initiation of therapy...

...liquid biopsy revealed additional increase of tumor molecular burden (somatic alteration burden, 16.4% v 12.2%), with persistence of FGFR1 amplification and reappearance of RAF-1 amplification, as well as the emergence of CDK6 amplification...An FDG-PET scan and a CT scan documented progression of disease...Compassionate use of the FGFR inhibitor ponatinib was requested, because of the unavailability of a selective FGFR inhibitor…Unfortunately, treatment was poorly tolerated...Ponatinib was discontinued after 12 weeks because of further disease progression with adrenal metastasis...

...liquid biopsy revealed additional increase of tumor molecular burden (somatic alteration burden, 16.4% v 12.2%), with persistence of FGFR1 amplification and reappearance of RAF-1 amplification, as well as the emergence of CDK6 amplification...Ponatinib was discontinued after 12 weeks because of further disease progression with adrenal metastasis, and nivolumab was started under compassionate use...The patient ultimately died in July 2018 as a result of clinical deterioration and further disease progression.

Retrospective analysis of the MEK2 mutations in serial plasma samples collected through the patient’s treatment course revealed emergence of these mutant alelles in concert with increases in fractional abundance of mutant BRAF and TP53 alleles (Figure 5E). Thus, these data likely reflect the emergence of heterogeneous polyclonal resistance mechanisms that evolved under the selective pressure of trametinib therapy.

...two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly....A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin...and a confirmed tumor response....LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Retrospective analysis of the MEK2 mutations in serial plasma samples collected through the patient’s treatment course revealed emergence of these mutant alelles in concert with increases in fractional abundance of mutant BRAF and TP53 alleles (Figure 5E). Thus, these data likely reflect the emergence of heterogeneous polyclonal resistance mechanisms that evolved under the selective pressure of trametinib therapy.