TEST:

FoundationOne® CDx

BRAFTOVIis a kinase inhibitor indicated:...in combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

Food and Drug Administration approved the fixed dose combination of niraparib and abiraterone acetate (Akeega, Janssen Biotech, Inc.), with prednisone, for adult patients with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved test.

Food and Drug Administration approved the fixed dose combination of niraparib and abiraterone acetate (Akeega, Janssen Biotech, Inc.), with prednisone, for adult patients with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved test.

...Food and Drug Administration approved olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test.

...Food and Drug Administration approved olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test.

TABRECTA is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

Innovent Biologics...announced that the National Medical Products Administration (NMPA) has approved Pemazyre® (pemigatinib) for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement as confirmed by a validated diagnostic test that have progressed after at least one prior line of systemic therapy.

Innovent Biologics...announced that the National Medical Products Administration (NMPA) has approved Pemazyre® (pemigatinib) for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement as confirmed by a validated diagnostic test that have progressed after at least one prior line of systemic therapy.

TRUSELTIQ is a kinase inhibitor indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

TRUSELTIQ is a kinase inhibitor indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated...for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:...for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: Ovarian cancer….in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either....genomic instability.

PEMAZYRE is a kinase inhibitor indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that...have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation.

VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that...have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation.

VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that...have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation.

GILOTRIF is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

Melanoma: Cutaneous...BRAF Targeted Therapies…Vemurafenib...Unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test

Melanoma: Cutaneous...BRAF/MEK Combinations…Vemurafenib/cobimetinib…Unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test

...NCCN Panel recommends BRAF inhibitor monotherapy only in those rare cases where combination therapy is contraindicated. In such cases, BRAF inhibitor monotherapy remains a treatment option especially if the patient is not an appropriate candidate for immune checkpoint inhibitor therapy. Dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib combination therapy regimens are FDA approved for the treatment of patients with unresectable or distant metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

NON-SUPPORTIVE EVIDENCE: In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053).

In the PIK3CA-alt cohort, ALP + FUL clinical benefit was seen across TMB quartiles (Q1: 0 -<2.52, Q2: 2.52 -<3.78, Q3: 3.78 -<5.04, Q4: ≥ 5.04 mut/megabase).

PFS prognosis (assessed in the placebo + CPB arm) was improved in patients with BRCA1/2m (hazard ratio [HR] 0.62, 95% CI 0.46–0.84) and HRD (HR 0.63, 95% CI 0.49–0.80) tumors. There was a suggested association between PD-L1+ and HRD (HRD prevalence: 40% vs 25% in PD-L1+ vs PD-L1– subgroups...

PFS prognosis (assessed in the placebo + CPB arm) was improved in patients with BRCA1/2m (hazard ratio [HR] 0.62, 95% CI 0.46–0.84) and HRD (HR 0.63, 95% CI 0.49–0.80) tumors. There was a suggested association between PD-L1+ and HRD (HRD prevalence: 40% vs 25% in PD-L1+ vs PD-L1– subgroups...

CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC....A trend toward OS benefit with nivolumab versus placebo was seen in patients with TMB ≥13 mut/Mb (HR, 0.67; 95% CI, 0.45 to 1.01; Fig 3A), but not in those with TMB <13 mut/Mb (HR, 0.92; 95% CI, 0.70 to 1.22; Fig 3B).

CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC....In the TMB-evaluable population, OS was improved with combination therapy versus placebo in patients with TMB ≥13 mut/Mb (HR, 0.61; 95% CI, 0.39 to 0.94; Fig 3A) but not in those with TMB<13 mut/Mb (HR, 1.04; 95% CI, 0.79 to 1.37; Fig 3B).

The dataset used for the clinical validation was from MYSTIC, which evaluated first-line durvalumab (anti-PD-L1 antibody) ± tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody) or chemotherapy for metastatic NSCLC....Using the new bTMB algorithm and an optimal bTMB cutoff of ≥20 mut/Mb, high bTMB was predictive of clinical benefit with durvalumab + tremelimumab versus chemotherapy.

...CNA in CDKN2A (12%) and CDKN2B (11%) were associated with improved PFS and OS clinical activity in the A + nP arm vs the P + nP arm (HR PFS, 0.43-0.44 and HR OS, 0.47, respectively).

...CNA in CDKN2A (12%) and CDKN2B (11%) were associated with improved PFS and OS clinical activity in the A + nP arm vs the P + nP arm (HR PFS, 0.43-0.44 and HR OS, 0.47, respectively).

The phase III DANUBE study assessed the efficacy of the PD-L1 inhibitor durvalumab (D), alone or in combination with the CTLA-4 inhibitor tremelimumab (T), versus standard of care chemotherapy (SoC) for the first-line treatment of unresectable, locally advanced or metastatic UC. Among 1032 patients randomised in DANUBE...For D vs SoC, bTMB and tTMB were not associated with OS or PFS at any cutoff. For D+T, stronger associations between bTMB and OS as well as PFS were observed with increasing bTMB cutoffs (table 1). At the bTMB cutoff ≥ 24 mut/Mb, 12-month OS rates were 76.7% for D+T and 54.3% for SoC, whereas for bTMB < 24 mut/Mb, 12-month OS rates were 53.4% for D+T and 51.2% for SoC. Similar trends for both OS and PFS were observed with tTMB. Both bTMB and tTMB are potentially useful biomarkers for enriching responses to D+T in previously untreated, advanced UC. Neither bTMB nor tTMB was associated with better outcomes for D monotherapy.

The phase III DANUBE study assessed the efficacy of the PD-L1 inhibitor durvalumab (D), alone or in combination with the CTLA-4 inhibitor tremelimumab (T), versus standard of care chemotherapy (SoC) for the first-line treatment of unresectable, locally advanced or metastatic UC. Among 1032 patients randomised in DANUBE...For D vs SoC, bTMB and tTMB were not associated with OS or PFS at any cutoff. For D+T, stronger associations between bTMB and OS as well as PFS were observed with increasing bTMB cutoffs (table 1). At the bTMB cutoff ≥ 24 mut/Mb, 12-month OS rates were 76.7% for D+T and 54.3% for SoC, whereas for bTMB < 24 mut/Mb, 12-month OS rates were 53.4% for D+T and 51.2% for SoC. Similar trends for both OS and PFS were observed with tTMB. Both bTMB and tTMB are potentially useful biomarkers for enriching responses to D+T in previously untreated, advanced UC. Neither bTMB nor tTMB was associated with better outcomes for D monotherapy.

...higher TMB was associated with OS benefit in PD-L1+ TNBC treated with Az + nP…

One-sided P values for the association of TMB and clinical outcomes in pembro-treated patients were 0.154 for ORR, 0.014 for PFS, and 0.018 for OS; the area under the ROC curve ([AUROC] 95% CI) for predicting ORR was 0.58 (0.43-0.73). Two-sided P values for the association of TMB and clinical outcomes in chemo-treated patients were 0.114 for ORR, 0.478 for PFS, and 0.906 for OS; AUROC (95% CI) was 0.43 (0.27-0.59).

PD-L1 IC2/3 was associated with significantly longer OS for atezo mono vs placebo + PBC and a combination of PD-L1 IC2/3, and high TMB (> 10 muts/Mb) identified a pt subset (≈ 14% of BEP) with particularly favorable outcomes with atezo mono vs placebo + PBC; similar results for PD-L1 and TMB were not seen with atezo + PBC vs placebo + PBC.

With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]….TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in gBRCA1m patients.

Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM, BAP1, FANCF, PALB2, and BRIP1...

Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM, BAP1, FANCF, PALB2, and BRIP1...

Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM, BAP1, FANCF, PALB2, and BRIP1...

Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM, BAP1, FANCF, PALB2, and BRIP1...

Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM, BAP1, FANCF, PALB2, and BRIP1...

The primary aims of this single-arm, phase 2 trial were to determine the objective response rate (ORR) of HPV-negative, LA-HNSCC to palbociclib, and to correlate responses to somatic CDKN2A alterations....The ORR with palbociclib was significantly higher in CDKN2A altered disease.

The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control….These findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC.

BL characteristics were generally similar between Part 1 (n = 60) and Part 2 (n = 170), and across tTMB and bTMB subgroups. At 12.5-mo minimum follow up, ORR in Part 1 was 30% and 39% in PD-L1 ≥1% (n = 30) and <1% (n = 28) subgroups, respectively. ORR by TMB (Parts 1 and 2 combined) is shown in the table....In CheckMate 592, high tTMB and bTMB were associated with better responses to 1L NIVO + IPI in pts with mNSCLC.

Alpelisib (ALP), an αselective PI3K inhibitor and degrader, demonstrated clinical benefit in combination with fulvestrant (FUL) in the SOLAR-1 study in pts with PIK3CA-mut HR+, HER2− ABC....we compare the gene alteration landscape in pts with altered (alt) and non-alt PIK3CA and the efficacy of ALP + FUL in pts whose tumors have alterations...Clinical benefit of ALP vs PBO was observed in pts with PIK3CA-alt disease who also had alterations in analyzed genes and/or genes associated with the MAPK pathway.

We conducted a single-arm phase II study to investigate the clinical benefits of adding Bev 15 mg/kg to Atez 1200 mg/body in first-line for patients with intermediate-high TBM≥10 mutation/megabase (mut/meg)....These positive results support the combination of Atez+Bev as a potential treatment option for non-Sq NSCLC with TBM≥10.

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.

...efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC....Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1)….The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting.

Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial....Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687).

Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial....Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687).

Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial....Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687).

Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial....Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687).

The efficacy population included 245 pts, 103 (85 TMB-H) in A1 and 142 (9 TMB-H) in A2....TMB-H status was more frequent in the dMMR pts, which is in line with known characteristics of these biomarkers.

Survival analysis showed that SPTA1mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes....SPTA1mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT.

...a pooled analysis of SPTA1mt (a core positive predictors of CD8+TILs) and KEAP1mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1mt and KEAP1mt had a compound effects for TIME. The validation showed that co mutation with SPTA1mtwas accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1mt patients.

...advanced solid tumors with TMB ≥10 mut/Mb by any CLIA-certified assay. Pts received atezolizumab…In the primary efficacy population of 42 pts with TMB ≥16 mut/Mb by F1CDx, confirmed investigator-assessed ORR was 38.1% vs 2.1% in 48 pts with TMB ≥10 mut/Mb and <16 mut/Mb; median DOR was not reached in either group. DCR was 61.9% vs 22.9%, respectively...

FIGHT-202 (NCT02924376), a phase II, open-label, multicenter, global study of pemigatinib in patients with previously treated advanced or metastatic cholangiocarcinoma...3 of the 4 patients treated with pemigatinib who had FGFR2 p.C382R mutations achieved a best overall response of stable disease, with a PFS of 6.9, 4.0, and 9.0 months.

Baseline tumor tissue from 308 pts (71%; intent-to-treat) was tested by FoundationOne®...In TNBC pts receiving TALA, OS was shorter with MYC amplification than without...

A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks...PIK3 mutants had a higher overall response rate (ORR) than the wild type (69.6% vs. 43.5%, OR 0.34; p=0.045; tables 3 and 4)….Median PFS was higher in the high TMB cohort compared to the low-intermediate group and reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05)...PFS improvement in patients with tumors expressing PDL1 trended towards statistical significance (median 18 vs. 40 weeks. HR=1.43. 95%CI 0.93, 4.46). BRAF mutation conferred shorter PFS (median 17 vs. 39 weeks. HR=0.35. 95%CI 0.14, 0.91) (figure 2).

A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks...PIK3 mutants had a higher overall response rate (ORR) than the wild type (69.6% vs. 43.5%, OR 0.34; p=0.045; tables 3 and 4)….Median PFS was higher in the high TMB cohort compared to the low-intermediate group and reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05)...PFS improvement in patients with tumors expressing PDL1 trended towards statistical significance (median 18 vs. 40 weeks. HR=1.43. 95%CI 0.93, 4.46). BRAF mutation conferred shorter PFS (median 17 vs. 39 weeks. HR=0.35. 95%CI 0.14, 0.91) (figure 2).

A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks...PIK3 mutants had a higher overall response rate (ORR) than the wild type (69.6% vs. 43.5%, OR 0.34; p=0.045; tables 3 and 4)….Median PFS was higher in the high TMB cohort compared to the low-intermediate group and reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05)...PFS improvement in patients with tumors expressing PDL1 trended towards statistical significance (median 18 vs. 40 weeks. HR=1.43. 95%CI 0.93, 4.46). BRAF mutation conferred shorter PFS (median 17 vs. 39 weeks. HR=0.35. 95%CI 0.14, 0.91) (figure 2).

Phase 2 TALAPRO-1...to assess germline/somatic origin of tumor DDRalt (tDDRalt) and associations with efficacy...The most common tDDRalt in the 37 pts were BRCA2 (11 germline; 7 somatic) and ATM (3 germline; 6 somatic). Observed ORR was numerically higher for pts with tDDRalt of germline origin (7/20 [35%]) than with only somatic DDRalt (1/16 [6.3%])...

Phase 2 TALAPRO-1...to assess germline/somatic origin of tumor DDRalt (tDDRalt) and associations with efficacy...The most common tDDRalt in the 37 pts were BRCA2 (11 germline; 7 somatic) and ATM (3 germline; 6 somatic). Observed ORR was numerically higher for pts with tDDRalt of germline origin (7/20 [35%]) than with only somatic DDRalt (1/16 [6.3%])...

On multivariate analysis, all 3 factors were independently and significantly associated with ≥PR: TMB ≥10 mutations/megabase (HR -4.254, p=2.1 x 10−5), low NLR (HR=2.591, p=0.00958) and absence of visceral metastasis status (HR=4.105, p=4.04 x 10−5).

Histologies that were TMB-high included melanoma (N = 6), bladder cancer (N = 2), cutaneous squamous cell carcinoma (N =2), glioblastoma (N = 1), breast cancer (N = 1), basal cell carcinoma (N = 1), esophageal carcinoma (N = 1), and prostate cancer (N = 1)...All patients were treated with either PD-1/L1 or CTLA4 checkpoint blockade (some received a combination of these agents)...The median PFS for TMB-high tumors compared to TMB-Low to -Intermediate tumors was 26.8 months vs. 4.3 months. (P = 0.0173, HR 0.42 [95% CI 0.22–0.77])...

Histologies that were TMB-high included melanoma (N = 6), bladder cancer (N = 2), cutaneous squamous cell carcinoma (N =2), glioblastoma (N = 1), breast cancer (N = 1), basal cell carcinoma (N = 1), esophageal carcinoma (N = 1), and prostate cancer (N = 1)...All patients were treated with either PD-1/L1 or CTLA4 checkpoint blockade (some received a combination of these agents)...The median PFS for TMB-high tumors compared to TMB-Low to -Intermediate tumors was 26.8 months vs. 4.3 months. (P = 0.0173, HR 0.42 [95% CI 0.22–0.77])...

Histologies that were TMB-high included melanoma (N = 6), bladder cancer (N = 2), cutaneous squamous cell carcinoma (N =2), glioblastoma (N = 1), breast cancer (N = 1), basal cell carcinoma (N = 1), esophageal carcinoma (N = 1), and prostate cancer (N = 1)...All patients were treated with either PD-1/L1 or CTLA4 checkpoint blockade (some received a combination of these agents)...The median PFS for TMB-high tumors compared to TMB-Low to -Intermediate tumors was 26.8 months vs. 4.3 months. (P = 0.0173, HR 0.42 [95% CI 0.22–0.77])...

Histologies that were TMB-high included melanoma (N = 6), bladder cancer (N = 2), cutaneous squamous cell carcinoma (N =2), glioblastoma (N = 1), breast cancer (N = 1), basal cell carcinoma (N = 1), esophageal carcinoma (N = 1), and prostate cancer (N = 1)...All patients were treated with either PD-1/L1 or CTLA4 checkpoint blockade (some received a combination of these agents)...The median PFS for TMB-high tumors compared to TMB-Low to -Intermediate tumors was 26.8 months vs. 4.3 months. (P = 0.0173, HR 0.42 [95% CI 0.22–0.77])...

Histologies that were TMB-high included melanoma (N = 6), bladder cancer (N = 2), cutaneous squamous cell carcinoma (N =2), glioblastoma (N = 1), breast cancer (N = 1), basal cell carcinoma (N = 1), esophageal carcinoma (N = 1), and prostate cancer (N = 1)...All patients were treated with either PD-1/L1 or CTLA4 checkpoint blockade (some received a combination of these agents)...The median PFS for TMB-high tumors compared to TMB-Low to -Intermediate tumors was 26.8 months vs. 4.3 months. (P = 0.0173, HR 0.42 [95% CI 0.22–0.77])...

Histologies that were TMB-high included melanoma (N = 6), bladder cancer (N = 2), cutaneous squamous cell carcinoma (N =2), glioblastoma (N = 1), breast cancer (N = 1), basal cell carcinoma (N = 1), esophageal carcinoma (N = 1), and prostate cancer (N = 1)...All patients were treated with either PD-1/L1 or CTLA4 checkpoint blockade (some received a combination of these agents)...The median PFS for TMB-high tumors compared to TMB-Low to -Intermediate tumors was 26.8 months vs. 4.3 months. (P = 0.0173, HR 0.42 [95% CI 0.22–0.77])...

Pembro is given 200mg q3w x3 cycles. Pathologic complete response (pT0) in ITT population is the primary endpoint (EP)….8/8 pts (100%) with DDR/RB1 GA and CPS≥21% achieved pT0.

Pembro is given 200mg q3w x3 cycles. Pathologic complete response (pT0) in ITT population is the primary endpoint (EP)….8/8 pts (100%) with DDR/RB1 GA and CPS≥21% achieved pT0.

A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.

Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer...Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously)...Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45).

Confirmed partial responses (PR) in RECIST criteria were experienced by two patients, both receiving intermittent AZD5363 dosing (480 mg 4 days on/3 days off and 640 mg 2 days on/5 days off). Tumor samples from these two responders were subjected to mutation profiling by next-generation sequencing and each was found to have AKT1E17K mutation in archival primary tumor.

High tTMB (≥16 mut/Mb) is associated with improved atezo response and DoR across NSCLC, mUC and melanoma and lines of therapy.

P demonstrated anti-tumor activity in heavily pre-treated MBC pts with HTMB.

A 54-year-old woman with left anterior chest pain had been diagnosed with left lower lung adenocarcinoma 11 years ago....Foundation One CDx revealed CD74-ROS1 fusion (Figure 4). Therefore, the patient was administered entrectinib as the ninth treatment line, which significantly reduced the right cervical lymphadenopathy and right lower tumors. She has been taking entrectinib for over 20 months now.

...we present a case of a 56-year-old woman diagnosed with KIF5B-MET fusion-positive non-small cell lung cancer who had a durable response to capmatinib after acquired resistance to telisotuzumab vedotin.

This 64-year-old male patient...whose path report showed lung adenocarcinoma. FoundationOne CDx panel demonstrated MET exon 14 skipping mutation (3038+3A>G, allelic fraction > 80%) plus MET amplification (12 copy numbers). PD-L1 expression (22C3) was 90%....Two months after tepotinib was started, complete radiologic response was achieved, and patient continues on treatment without evidence of disease after 1 year.

...we report a case of MYH9-ROS1 fusion gene-positive lung adenocarcinoma...As the disease worsened, another genetic test was conducted using FoundationOne® CDx, and the MYH9-ROS1 fusion gene was detected. Multiple lung metastases disappeared after the administration of entrectinib; the response persisted up to a year.

...a 67-year-old man was diagnosed with stage IV pulmonary poorly differentiated adenocarcinoma...NGS by FoundationOne® CDx revealed KIAA1549-BRAF fusion (Figure 1) and MET amplification...the treatment strategy was shifted to combination therapy with dabrafenib, trametinib, and capmatinib after multidisciplinary team discussion. Finally, the right pleural effusion subsided and remained stable for more than 6 months.

Two patients showed EGFR A763_Y764insFQEA, which has been considered as sensitive to classical EGFR tyrosine kinase inhibitors (EGFR-TKIs). Two patients (EGFR A763_Y764insFQEA and EGFR T751_I759>S) had received erlotinib during their treatment course and both of them showed stable disease with a progression-free survival of 5.9 and 10.1 months, respectively.

Two patients showed EGFR A763_Y764insFQEA, which has been considered as sensitive to classical EGFR tyrosine kinase inhibitors (EGFR-TKIs). Two patients (EGFR A763_Y764insFQEA and EGFR T751_I759>S) had received erlotinib during their treatment course and both of them showed stable disease with a progression-free survival of 5.9 and 10.1 months, respectively.

Two patients showed EGFR A763_Y764insFQEA, which has been considered as sensitive to classical EGFR tyrosine kinase inhibitors (EGFR-TKIs). Two patients (EGFR A763_Y764insFQEA and EGFR T751_I759>S) had received erlotinib during their treatment course and both of them showed stable disease with a progression-free survival of 5.9 and 10.1 months, respectively.

...case of a 45-year-old Japanese woman with NSCLC positive for EGFR-KDD (duplication of exons 18–25) who developed carcinomatous meningitis and showed a marked response to the EGFR-TKIs erlotinib and osimertinib.

...case of a 45-year-old Japanese woman with NSCLC positive for EGFR-KDD (duplication of exons 18–25) who developed carcinomatous meningitis and showed a marked response to the EGFR-TKIs erlotinib and osimertinib.

Tumor analysis with FoundationOne CDx (Foundation Medicine, Inc. Cambridge, MA) demonstrated a PD-L1 tumor proportion score of 70%, Microsatellite Instability–High (MSI-H) status, and a tumor mutational burden of 49 mutations per megabase...Interval CT scan after 2 cycles of pembrolizumab showed decreased mass size at 3.6×3.8×3.8cm. Serum CA 19–9 had decreased to 27.7 U/mL. Repeat imaging after a total of 4 cycles showed further tumor volume decrease (3.2×2.7×3.1 cm) and cystic degeneration...

A 37-year old man with Pca...The patient underwent 19 courses of docetaxel (60 mg/m2) and five courses of cabazitaxel (25 mg/m2) thereafter. Docetaxel reduced the PSA by 85%; however, cabazitaxel induced no PSA response. After the disease progressed while the patient underwent taxane-based chemotherapy, we performed a genetic test by FoundationONE CDx...Genetic testing revealed a frameshift mutation with a stop codon two positions further in the BRCA2 (pA902fs*2)...

A 37-year old man with Pca...Bicalutamide and salvage radiation therapy (SRT) for the prostatic fossa (66 Gy) were introduced. Twenty-five months later, the PSA had decreased...then gradually rose to 11.0 ng/ml despite the addition of leuprorelin acetate followed by abiraterone...After the disease progressed while the patient underwent taxane-based chemotherapy, we performed a genetic test by FoundationONE CDx...Genetic testing revealed a frameshift mutation with a stop codon two positions further in the BRCA2 (pA902fs*2)...

A 37-year old man with Pca...After the disease progressed while the patient underwent taxane-based chemotherapy, we performed a genetic test by FoundationONE CDx...Genetic testing revealed a frameshift mutation with a stop codon two positions further in the BRCA2 (pA902fs*2)...Thus, we administered cisplatin, the only platinum drug approved to treat PCa...Thereafter, the PSA continued to decrease...This case suggests potential predictive role of BRCA2 mutation for cisplatin in patients with mCRPC.

A CT-guided biopsy of the lung lesion revealed undifferentiated carcinoma with spindle cell malignant neoplasm with osteoclast-like giant cells consistent with UCOGC...While the patient was undergoing IMRT, tissue from her lung metastasis was sent for NGS (FoundationOne, Foundation Medicine), which revealed alterations to the BRAF oncogene and the tumor suppressor genes NF1, PIK3A, CDKN2A, TERT promoter, and TP53. The tumor was microsatellite-stable with a high TMB (32 mutations per megabase [mut/Mb])...The patient continued pembrolizumab cycles 8 through 19 with continued reduction of the pancreatic primary and brain metastasis and complete resolution of the pulmonary metastasis biopsied at diagnosis. Cycles 20 through 46 showed continued response in all lesions...

A 75-year-old Japanese female never-smoker was presented with a small lung 66 nodule in the right upper lobe...sequencing analysis of the 79 biopsy specimens with FoundationOne®CDx and it revealed a MET exon 14 skipping mutation...She was treated with oral capmatinib at a dose of 400 mg twice daily. However, after the treatment for 6 days, mild cough and dyspnea developed and a chest X ray and CT scan showed widespread ground-glass opacities in both lungs...

A 75-year-old Japanese female never-smoker was presented with a small lung 66 nodule in the right upper lobe...sequencing analysis of the 79 biopsy specimens with FoundationOne®CDx and it revealed a MET exon 14 skipping mutation...We administered tepotinib at a low starting dose of 250mg once daily under careful observation. After 7 weeks, we confirmed efficacy with shrinkage of the enlarged lymph nodes...

FIGHT-202 (NCT02924376), a phase II, open-label, multicenter, global study of pemigatinib in patients with previously treated advanced or metastatic cholangiocarcinoma...One of 8 patients with FRS2 amplifications achieved stable disease.

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...

Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease....This case suggests that larotrectinib is not only effective in NTRK fusions but may be efficacious in cases with gene amplification.

Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease....This case suggests that larotrectinib is not only effective in NTRK fusions but may be efficacious in cases with gene amplification.

Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease....This case suggests that larotrectinib is not only effective in NTRK fusions but may be efficacious in cases with gene amplification.

Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively)...She had a partial response (PR) although on crizotinib but developed progression after 5 months. She was then enrolled onto the phase 1 dose escalation portion of the alectinib trial...

Another biopsy was performed on a progressing liver lesion and the tissue was sent for NGS using Foundation One CDx testing. This biopsy revealed the emergence of the EGFRT790M mutation (allelic frequency of 59%). Interestingly, this was accompanied by an increase in the allelic frequency of the L718V mutation (80%), and a decrease in the frequency of the L718Q mutation (3%). This report suggests that while L718Q/V mutant tumors could benefit from transient responses to afatinib treatment, they can acquire the T790M mutation and eventually become resistant to all available EGFR TKIs.

Another biopsy was performed on a progressing liver lesion and the tissue was sent for NGS using Foundation One CDx testing. This biopsy revealed the emergence of the EGFRT790M mutation (allelic frequency of 59%)...Interestingly, this was accompanied by an increase in the allelic frequency of the L718V mutation (80%), and a decrease in the frequency of the L718Q mutation (3%)...This report suggests that while L718Q/V mutant tumors could benefit from transient responses to afatinib treatment, they can acquire the T790M mutation and eventually become resistant to all available EGFR TKIs.

Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively)...She had a partial response (PR) although on crizotinib but developed progression after 5 months. She was then enrolled onto the phase 1 dose escalation portion of the alectinib trial...

Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively)...She had a partial response (PR) although on crizotinib but developed progression after 5 months. She was then enrolled onto the phase 1 dose escalation portion of the alectinib trial...

Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively)...She had a partial response (PR) although on crizotinib but developed progression after 5 months. She was then enrolled onto the phase 1 dose escalation portion of the alectinib trial...

In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro…. In this brief report, we identified a novel acquired secondary ALK mutation (ALK F1174V) in an ALK+ NSCLC patient who progressed on crizotinib and demonstrated that a previously described secondary mutation, ALK G1202R, confers high level of intrinsic resistance to alectinib...

Biopsy of a liver lesion demonstrated adenocarcinoma positive for TTF-1 and Napsin-A by immunohistochemistry. An EGFRL858R mutation was detected in the tumor with targeted NGS using the Illumina MiSeqDx platform...she was started on 80 mg osimertinib QD. She had an excellent response, with shrinkage of all sites of disease and resolution of brain metastases.Imaging performed every ~2 months showed a continued response, until 8.5 months after initiation of osimertinib when the patient was found to have growth of a liver lesion.

...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.

...alterations in TYRO3 by FoundationOne, and the discovery of mutations in ALK in the COA109 PDX...there was no significant difference between the tumor growth rate of the control treated group and those treated with crizotinib (Fig. 6A, B). Sunitinib alone significantly delayed COA109 tumor growth (p ≤ 0.001, Fig. 6A, B). Further, the addition of sunitinib to crizotinib diminished tumor growth compared to the control (p ≤ 0.05) and crizotinib treated groups, but not to sunitinib alone.

...alterations in TYRO3 by FoundationOne, and the discovery of mutations in ALK in the COA109 PDX...there was no significant difference between the tumor growth rate of the control treated group and those treated with crizotinib (Fig. 6A, B). Sunitinib alone significantly delayed COA109 tumor growth (p ≤ 0.001, Fig. 6A, B). Further, the addition of sunitinib to crizotinib diminished tumor growth compared to the control (p ≤ 0.05) and crizotinib treated groups, but not to sunitinib alone.

...alterations in TYRO3 by FoundationOne, and the discovery of mutations in ALK in the COA109 PDX...there was no significant difference between the tumor growth rate of the control treated group and those treated with crizotinib (Fig. 6A, B). Sunitinib alone significantly delayed COA109 tumor growth (p ≤ 0.001, Fig. 6A, B). Further, the addition of sunitinib to crizotinib diminished tumor growth compared to the control (p ≤ 0.05) and crizotinib treated groups, but not to sunitinib alone.