Patients must have had HER2 testing performed on the primary breast tumor before neoadjuvant chemotherapy according to the current ASCO/CAP guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer; patients who have a primary tumor that is either HER2-positive or HER2-negative are eligible
No prior anti-epidermal growth factor (EGF) or anti-human epidermal growth factor receptor 2 (HER2) therapy
Only for the 1L Cohort: human epidermal growth factor receptor 2 (HER2)-negative tumors;
For Part B exclusively (RO6874281 in combination with trastuzumab), participants with metastatic or recurrent or locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as defined by the College of American Pathologists HER2 testing guidelines, who have progressed on at least two lines of HER2-directed therapies in the metastatic setting and the last therapy prior to going on study has to contain a HER2-directed antibody; baseline left ventricular ejection fraction (LVEF) of >=50% (measured by echocardiography) predose on Cycle 1 Day 1
Patients who have received prior therapy with any irreversible human epidermal growth factor receptor tyrosine kinase inhibitor
Have a diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer for Parts A to E, G, and I.
Have a diagnosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer for Parts F and H.
Have a diagnosis of Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) breast cancer • Prior combined CDK 4/6 inhibitor and endocrine therapy and 1 or 2 prior lines of chemotherapy
Part 2, Cohort 5, Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer who have failed prior treatment with a CDK 4/6 inhibitor in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy.
Prior chemotherapy, prior epidermal growth factor receptor (EGFR) targeted therapy, or prior radiation therapy for HNSCC
Patients with metastatic colorectal cancer who have progressed on, or are ineligible for standard therapy such as fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and anti-epidermal growth factor receptor (EGFR) antibodies where appropriate, but are suitable candidates for regorafenib treatment
No prior epidermal growth factor receptor (EGFR) inhibitor or antiangiogenic agent allowed
Locally tested, Human Epidermal Growth Factor Receptor 2 (HER2)-expressing BC
Radiographic documentation of disease progression while on previous continuous treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
For triple-negative breast cancer, a minimum of 1 prior cytotoxic chemotherapy regimen must have been administered for the indication of metastatic disease.Depending on receptor status, 1 or 2 prior cytotoxic regimens are required prior to enrollment in this trial; hormonal and/or human epidermal growth factor receptor 2 (HER2) -targeted agents may be required.
Must have a confirmed Epidermal growth factor receptor amplification in tumor tissue
Patients with recent (within 15 days preoperatively) history deteriorate kidney function (creatinine serum concentrations > 2.5 mg/dL or epidermal growth factor receptor [eGFR] < 30 mL/kg/min)
Histologically or cytologically confirmed solid tumor of one of the following types associated with overexpression of Epidermal Growth Factor Receptor (EGFR) or EGFR ligands: Dose Escalation Phase:
Have documented testing for human epidermal growth factor receptor 2 (HER2-neu) overexpressing, and for those with tumors overexpressing HER2-neu, have documented progression on Trastuzumab-containing therapy
Epidermal growth factor receptor (eGFR) < 50 by Mayo or Cockcroft formula
Patients with known ponatinib-resistant gene alterations\r\n* Platelet derived growth factor receptor, alpha polypeptide (PDGFRA) D842V mutation\r\n* Mast/stem cell growth factor receptor Kit (cKIT) D816V mutation\r\n* FLT3 D835V/Y/H/F or Y842C mutations\r\n* Fibroblast growth factor receptor 3 (FGFR3) K652E mutation
Histologically confirmed diagnosis of advanced (metastatic or unresectable) non-small cell lung cancer (NSCLC) with mutations, rearrangement and fusion involving RET oncogene, or abnormalities in the pazopanib target genes defined as vascular endothelial growth factor receptors 1-3 (VEGFR1-3), platelet-derived growth factor receptor-alpha (PDGFRA), or platelet-derived growth factor receptor-beta (PDGFRB), or tumor protein p53 (TP53) with abnormalities including deletion, insertion, early stop codon, and/or nonsynonymous mutations with functional consequences; Clinical Laboratory Improvement Act (CLIA) certified lab testing for pazopanib target genes using cell free deoxyribonucleic acid (DNA) from peripheral blood and/or assays performed on tumor tissues are acceptable
COHORT II: Core tissue must have human epidermal growth factor receptor 2 (HER 2) testing
Human epidermal growth factor receptor 2 (HER2)-neu positive
Have either human epidermal growth factor receptor 2 positive (HER2+) (Study Part A) or HER2- (Study Part B) breast cancer.
Previous treatment with an histone deacetylase inhibitor or an epidermal growth factor receptor inhibitor within at least 4 weeks of the date of first administration of study drug
Tumors must demonstrate epidermal growth factor receptor (EGFR) amplification.
Patient must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for epidermal growth factor receptor (EGFR) analysis and for oropharyngeal cancer patients, human papilloma virus (HPV) analysis
Prior treatment with tyrosine-kinase inhibitors targeting VEGF, platelet-derived growth factor, fibroblast growth factor, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2 (TIE-2), or angiopoietin (or their receptors)
Patients who are found to have a cancer positive for the marker human epidermal growth factor receptor 2 (HER-2)/neu (Note: this exclusion criterion applies only to patients at the New York University [NYU] Tisch and Bellevue sites where there is currently a protocol open and available for patients who are HER-2/neu positive; this exclusion criterion does not apply to patients at the South Africa site)
Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer or ovarian cancer should have received at least two lines of systemic therapy in the advanced setting
Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody or small molecule)
Prior therapy with any agent targeting the HER2 pathway or human epidermal growth factor receptor 1 (HER1) (epidermal growth factor receptor [EGFR]) pathway
Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway
Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody or small molecule)
Patients who have received prior therapy with trastuzumab or any other anti-epidermal growth factor type II receptor antibody
Plan to administer any other systemic antitumor including endocrine therapy except for following standard of care treatment:\r\n* Trastuzumab at standard dosing human epidermal growth factor receptor 2 (HER2) positive tumors\r\n* Denosumab or bisphosphonates to treat metastatic bone disease
Tumor shown to be human epidermal growth factor 2 plus (HER2+)
Prior treatment with anti-epidermal growth factor receptor (EGFR) therapy (either panitumumab or cetuximab)
Absence of known epidermal growth factor receptor (EGFR) mutation
Human epidermal growth factor receptor 2 (HER2)-negative tumor (primary tumor or metastatic lesion)
Human Epidermal Growth Factor Receptor 2 (HER2)-positive gastric cancer
have received prior second-line treatment with oxaliplatin and/or irinotecan, and no other licensed/standard-of-care therapies are available. If the participant has RAS wild type colorectal cancer, he or she also must have received prior treatment with an epidermal growth factor receptor monoclonal antibody
Patients with the factor interacting with poly(A) polymerase alpha (PAPOLA) and cleavage and polyadenylation specific factor 1 (CPSF1) (FIP1L1)-platelet-derived growth factor receptor, alpha polypeptide (PDGFRalpha) fusion even with resistance to imatinib (such patients are no longer defined as systemic mastocytosis by the WHO)
Participants with human epidermal growth factor receptor 2 (HER2)-positive status.
Have a diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer
Prior therapy with agents targeting Insulin Growth Factor (IGF) and/or Insulin Growth Factor Receptor (IGFR) pathway.
Invasive ductal, lobular, medullary, papillary, colloid (mucinous), tubular histologies, or mixed histologies (lesions =< 2 cm) that are estrogen or progesterone receptor positive and do not exhibit human epidermal growth factor receptor 2 (HER2)/neu gene amplification OR ductal carcinoma in situ (lesions =< 2 cm)
Pathologic (histologically or cytologically) documented extracranial diagnosis of primary lung cancer, melanoma, human epidermal growth factor receptor 2 (HER2)-amplified or immuno-positive breast cancer, or HER2-amplified or immuno-positive gastric cancer, with brain metastasis detected by contrast enhanced magnetic resonance imaging (MRI) or computed tomography (CT) is required; patients with concurrent leptomeningeal diseases are eligible
Human epidermal growth factor receptor 2 (HER-2) status may be pending at initiation of FOLFIRINOX, but must be known prior to starting trastuzumab; if HER-2 is positive, patients must have a left ventricular ejection fraction (LVEF) >= 50%; HER-2 negative patients are not excluded
Documentation of human epidermal growth factor receptor 2 (HER2)-negative tumor.
The patient must have a pathologically confirmed (by histology, cytology, or immunohistology) diagnosis of TNBC (a cancer that does not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase), which is currently advanced/metastatic disease.
Human epidermal growth factor receptor 2 (HER-2) positive esophagogastric cancer; patients with unknown HER2 status are permitted
Known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy
Participants must have histologically confirmed hormone receptor positive (HR+), human epidermal growth factor 2 (HER2) negative stage II or stage III invasive breast cancer; evaluation for metastatic disease is not required in the absence of symptoms
If Human Epidermal Growth Factor Receptor (HER2) positive, subjects must have received and progressed on at least one prior standard HER2 directed therapy or the subject must be ineligible to receive anti-HER2 therapy.
Prior treatment with an investigational or marketed inhibitor of the epidermal growth factor receptor (EGFR) pathway or an Aurora Kinase inhibitor
Patients with mutations in the epidermal growth factor receptor (EGFR) gene; the mutational status of all patients with adenocarcinoma and non-squamous histology will be determined prior to study entry
Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues.
Prior treatment with epidermal growth factor receptor targeting small molecules or antibodies.
Prior anti-epidermal growth factor receptor antibody therapy (e.g. panitumumab or cetuximab) or prior small molecule anti-epidermal growth factor receptor therapy (e.g. erlotinib) for adenocarcinoma of the small bowel or ampulla of Vater
Gastric cancer (including gastric and EGJ cancers): at least 2 prior systemic regimens in adjuvant, advanced, or metastatic setting and, as appropriate, a human epidermal growth factor receptor 2 (HER2) targeted agent.
Prior treatment with a PI3K/mTOR inhibitor, epidermal growth factor receptor (EGFR) inhibitor, and/or necitumumab.
Subjects that are known to be epidermal growth factor (EGFR)-activating mutation positive must have received an EGFR inhibitor.
Tumor tissue available for epidermal growth factor receptor (EGFR) expression analysis
Prior treatment with tyrosine-kinase inhibitors targeting VEGF, platelet-derived growth factor, fibroblast growth factor, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2 (TIE-2), or angiopoietin (or their receptors)
Epidermal growth factor receptor (EGFR) mutations
Human epidermal growth factor receptor 2 (HER2)/neu negative on the core biopsy analysis defined as 0 or 1+ by immunohistochemistry or not amplified by fluorescent in situ hybridization analysis
Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules, EGFR-targeted antibodies, and/or any investigational agents for HNSCC
Human epidermal growth factor receptor 2 (HER2) normal (immunohistochemistry [ICH] 0-1; fluorescence in situ hybridization [FISH] < 2.0)
Adequate tissue for central immunohistochemical (IHC) assay of Met receptor, and epidermal growth factor receptor (EGFR) testing if EGFR status is unknown
There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/or radiation, with the exception of hormonal therapy for prostate and breast cancers, human epidermal growth factor receptor (HER)2-directed therapy for HER2+ breast cancer (3+ immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]+), and erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancer in the expansion cohort; there should be a minimum of 6 weeks from any prior antibody therapies, (such as ipilimumab or anti-programmed cell death [PD]1/programmed death-ligand [PDL]1)
Prior therapy targeting the epidermal growth factor receptor (EGFR) pathway
Unknown epidermal growth factor receptor (EGFR)mutation status or previously known EGFR mutated status in patients with adenocarcinoma.
Prior treatment with an investigational or approved agent for the purpose of inhibiting human epidermal growth factor receptor (HER) family members. This includes, but is not limited to, cetuximab, panitumumab, erlotinib, gefitinib, and lapatinib
Prior treatment with an epidermal growth factor receptor (EGFR) inhibitor is allowed if it was administered as part of definitive therapy for locally advanced disease and completed/terminated >/= 3 months before study enrollment
Patients who received prior phosphoinositide-3-kinase (PI3K) inhibitor or anti-receptor tyrosine-protein kinase erbB-3 (ERBB3 or HER3) antibody treatment, including bi-specific antibodies with HER3 as one of the targets (patients with prior exposure to pertuzumab or epidermal growth factor receptor (EGFR)-targeted agents are eligible)
Patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer are also excluded from this portion of the study
Subjects must have a solid tumor type likely to over-express Epidermal Growth Factor Receptor (EGFR) (Phase 1)
Prior treatment with investigational drugs that target the human growth factor (HGF) or MET pathway
Prior treatment with any anti-HER3 (Human Epidermal growth factor Receptor 3) treatment
Results of endothelial growth factor receptor (EGFR)-activating mutation testing
Epidermal growth factor receptor (EGFR)-mutation-positive disease according to local laboratory testing
Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules
The participant has a history of treatment with other agents targeting the Insulin-like or Epidermal Growth factor receptors.
Human epidermal growth factor receptor 2 (HER-2)/neu negative (phase II)
Paraffin-embedded tumor tissue from primary tumor or metastasis for determination of epidermal growth factor receptor expression and biomarker testing
Prior use of any monoclonal antibodies directly targeting the epidermal growth factor receptor (EGFr). Subjects who have received prior tyrosine kinase inhibitors such as gefitinib or erlotinib are eligible.
Treatment plan that includes any neoadjuvant or adjuvant therapy (either in the context of standard treatment or a clinical trial and including chemotherapy, treatments targeting the human epidermal growth factor receptor protein 2 [HER2]), hormonal therapy, or radiation; patients can receive any/all of these therapy components while on study in any combination
Completed adjuvant taxane-based chemotherapy as single agents or in combination with platins or human epidermal growth factor receptor 2 (HER-2) directed therapy
Patients must have a diagnosis of colorectal or lung cancer and be planning to receive one of the following human epidermal growth factor receptor (HER1)/epidermal growth factor receptor (EGFR) inhibitor therapies listed below for at least 6 weeks:\r\n* Cetuximab 400 mg/m^2 loading dose, 250 mg/m^2 weekly\r\n* Cetuximab 500 mg/m^2 every 2 weeks\r\n* Panitumumab 6 mg/kg every 2 weeks\r\n* Erlotinib 100-150 mg daily\r\n* Other HER1/EGFR inhibitor therapies, schedules, or doses of the above listed agents are not allowed\r\n* NOTE: concurrent chemotherapy and other anti-cancer therapies (such as carboplatin, paclitaxel, and bevacizumab) are allowed EXCEPT for the following chemotherapeutic agents which are known to cause skin rash that could interfere with EGFRI-induced skin toxicity assessment: gemcitabine, capecitabine, and topical fluorouracil (Efudex, Fluoroplex, Carac)
Subject is currently on anti-EGFR (human epidermal growth factor receptor) therapy, such as Iressa (gefitinib) or Erbitux (cetuximab, C225)
Have histologic diagnosis of human epidermal growth factor receptor 2 (HER2) positive (+) breast carcinoma
Histological or cytological confirmation of hormone-receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer
Patients must have had HER2 testing performed on the primary breast tumor collected prior to neoadjuvant chemotherapy according to the current ASCO/CAP guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer; patients who have a primary tumor that is HER2-positive, HER2-equivocal, or HER2-negative are eligible
Patient must NOT have human epidermal growth factor-2 positive (HER2+) metastatic disease
Impaired renal function defined as epidermal growth factor receptor (eGFR) < 50 mL/min/1.73m2
Patients with human epidermal growth factor-2 positive (HER2+) metastatic tumors are NOT eligible.
Patient must NOT be planning to receive everolimus nor human epidermal growth factor receptor 2 (HER2) directed therapy in addition to endocrine therapy.
Participants must have histologically or cytologically confirmed human epidermal growth factor receptor 2 (HER2) negative invasive breast adenocarcinoma
Histologic diagnosis of triple negative or human epidermal growth factor receptor 2 (HER2) amplified breast cancer, clinical stage T1-4, N0-3, M0/1 receiving preoperative systemic therapy and planned surgery
Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (results ascertained in centrally as part of ALCHEMIST-SCREEN protocol)
Patients must not have a known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion; EGFR/ALK testing is not required prior to registration and is included in the Foundation Medicine Incorporated (FMI) testing for screening/prescreening
Disease must be anaplastic lymphoma kinase (ALK) positive (defined by local institutional standards)
Tumors with driver mutations (epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive) treated with a tyrosine kinase inhibitor or crizotinib are eligible. For participants who have progressed on a tyrosine kinase inhibitor or crizotinib or are intolerant to this targeted therapy, that participant must receive platinum-based therapy prior to enrollment in this study. Documentation of such mutations must be available and entered into the electronic case report form (eCRF).
Patients with nonsquamous NSCLC having functionally significant anaplastic lymphoma kinase (ALK) translocations or epidermal growth factor receptor (EGFR) mutations who have not received prior treatment with ALK or EGFR inhibitor.
Histologically or cytologically confirmed diagnosis of stage IV NSCLC without epidermal growth factor receptor (EGFR)-sensitizing mutation, ROS1 and/or anaplastic lymphoma kinase (ALK) translocation
Participants with known anaplastic lymphoma kinase (ALK) translocations which are sensitive to available targeted inhibitor therapy are excluded
Patients must have high PD-L1 expression (Tumor Proportion Score [TPS] ? 50%) as determined by FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. First- or Second-line UROTHELIAL CARCINOMA (atezolizumab only)
Histologically confirmed non-squamous NSCLC; patients with adenocarcinoma must have had epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational testing; those with an actionable mutations/rearrangements are excluded
Study participants must have had prior epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing; participants with sensitizing mutations in EGFR or ALK rearrangements will be excluded
Has a tumor that harbors an epidermal growth factor receptor (EGFR)-sensitizing (activating) mutation or an anaplastic lymphoma kinase (ALK) translocation
Patients who are known to have somatic tumor mutations in the following genes, for which targeted agents are available that directly affect the treatment of brain metastasis: Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ROS-1 proto-oncogene, and proto-oncogene B-RAF
Subjects must have received 1 or more prior systemic therapies for this disease, (this can include neo-adjuvant or adjuvant chemotherapy if administered < 2 years prior to study enrollment), should not have had prior treatment with immunotherapy; (including immune checkpoint inhibitor drugs, or immunotherapy vaccines); patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations will need to have progressed on a tyrosine kinase inhibitor (TKI) treatment
(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of Stage IV squamous NSCLC and have not received prior chemotherapy or immunotherapy for metastatic disease and are not known to be PD-L1 positive (known high PD-L1 expression defined as Tumor Proportion Score [TPS] greater than or equal to 50%). Patients with known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene must have received at least 1 and up to 2 targeted therapies prior to enrollment.
Subjects with epidermal growth factor (EGFR) activating mutations, EGFR T790M or anaplastic lymphoma kinase gene re-arrangement must have received prior standard of care and have evidence of disease progression.
Histologically or cytologically confirmed diagnosis of stage IV NSCLC without epidermal growth factor receptor (EGFR)-sensitizing mutation, ROS1 and/or anaplastic lymphoma kinase (ALK) translocation.
Patients with an active oncogenic driver (e.g., epidermal growth factor [EGFR], activin-receptor-like kinase 1 [ALK1], or the proto-oncogene tyrosine-protein kinase ROS-1) must have progressed on or after a US Food and Drug Administration (FDA)- approved therapy for that aberration (Note: Previous treatment with a tyrosine kinase inhibitor and platinum-based doublets does not exclude the patient.).
Subjects with known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase receptor (ALK) or ROS1 gene rearrangements must have failed (progressive disease or unacceptable toxicity) at least one prior EGFR or ALK or ROS1 tyrosine kinase inhibitor, respectively. Subject may have received PD-1 or PDL-1 inhibitors and or chemotherapy. There is no limit on lines of prior anti-cancer therapy (a washout period applies for recent anti-cancer treatments).
Subjects must have received prior platinum doublet based treatment\r\n* Up to 2 lines of prior systemic therapy for metastatic disease are permitted\r\n* Adjuvant chemotherapy or concurrent chemoradiation for early stage disease does not count as prior therapy unless subject progressed within 6 months of completion of regimen\r\n* Patients with known activating mutations in epidermal growth factor receptor (EGFR), or known translocation in anaplastic lymphoma kinase (ALK) or ROS-1 are eligible provided they have progressed on or were intolerant to Food and Drug Administration (FDA) approved targeted therapy
Subjects with histologically or cytologically-confirmed metastatic NSCLC whose disease progressed during/after treatment with at least one platinum-containing chemotherapy regimen; patients whose tumors are known to harbor an exon 19 deletion or exon 21 L858R epidermal growth factor receptor (EGFR) mutation must have progressed on or had intolerance to an EGFR tyrosine kinase inhibitor; patients whose tumors are known to harbor an anaplastic lymphoma kinase (ALK) translocation must have progressed on or had intolerance to an ALK inhibitor
INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations must have been treated on at least one line of molecularly targeted therapy (e.g., erlotinib, crizotinib)
Tumor exhibits epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) re-arrangement that qualifies the patient for treatment with a systemic agent targeting these mutations
Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to Tyrosine-Kinase Inhibitor (TKI) (EGFR exon 18-21) or Anaplastic Lymphoma Kinase (ALK) rearrangement.
Have undergone appropriate standard of care treatment options (in the opinion of the treating investigator); patients with NSCLC must have undergone epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) testing and have received appropriate initial therapy
Patients must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is advanced/metastatic (stage IIIB/IV) or recurrent (progression after surgery or radiation or chemo-radiation treatment for loco-regional disease); patients with epidermal growth factor (EGFR) mutation, anaplastic lymphoma kinase (ALK) gene rearrangement or ROS1 translocation must have received an approved EGFR, ALK, or reactive oxygen species (ROS)1-directed therapy and have signs of disease progression prior to receiving pembrolizumab
Sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS-1) mutations are either negative or unknown
Patients must have histologically or cytologically confirmed diagnosis of stage IIIB or stage IV of non-small cell lung cancer and have received at least two lines of Food and Drug Administration (FDA)-approved or National Comprehensive Cancer Network (NCCN) accepted systemic therapy and progressed through, or not tolerated, such therapy; all subjects which harbor specific mutations, such as endothelial growth factor receptor (EGFR) deletion mutation of anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements, for which an acceptable targeted therapy exists, at least one of the lines of therapy must be such targeted therapy, unless the subject is not a candidate for the targeted therapy or unable to tolerate that therapy as determined by the treating physician\r\n* Subjects whose tumors harbor an exon 19 deletion or exon 21L858R EGFR mutation must have progressed on or had intolerance to EGFR tyrosine kinase inhibitor\r\n* Subjects whose tumors harbor an AKL translocation must have progressed on or had intolerance to crizotinib (or any FDA approved ALK inhibitor) OR
Patients with lung cancer whose tumors contain activating epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement should be excluded from this study, unless disease has progressed on all available, approved therapies targeting the EGFR mutation or ALK rearrangement
Known activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation
Participants must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with any actionable mutation or translocation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c-ros oncogene 1 (ROS1)
Histologically confirmed unresectable solid tumor malignancy with at least 1 measurable lesion in dose escalation; in the expansion phase, eligibility limited to metastatic triple negative breast cancer that has received prior taxane and anthracycline therapy; metastatic non-small cell lung cancer (NSCLC) that is not anaplastic lymphoma kinase positive (ALK+) and does not have a epidermal growth factor receptor (EGFR) sensitizing mutation; and metastatic gastric cancer
Patients must have tumor tissue available for submission that is sufficient to complete c-MET fluorescence in situ hybridization (FISH) studies as well as routine molecular profiling at the University of Pittsburgh Medical Center (UPMC); patients must agree to submission of these specimens\r\n* c-MET amplification will be determined by FISH ratio (c-MET/chromosome 7 centromere probe [CEP7]) > 2.0, based on testing of the primary tumor and/or site of metastatic disease\r\n* Patients’ tumors must undergo testing for epidermal growth factor receptor (EGFR) exon 19 deletion, EGFR exon 21 leucine substitution at position 858 (L858R) substitution, and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements; if positive, patients must have been treated with an appropriate tyrosine-kinase inhibitor (TKI) prior to enrolling to the study
Has confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1- (ROS1-), or B isoform of rapidly accelerated fibrosarcoma- (B-Raf-) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements)
Patients with tumors tested positive for Epidermal growth factor receptor (EGFR) gene mutations, Anaplastic lymphoma kinase (ALK) gene translocations, or C-ros oncogene receptor tyrosine kinase(ROS1) fusions
Life expectancy greater or equal to 3 months, as determined by the investigator -Patients must have progressed on the standard therapy, including platinum based - chemotherapy. Patients with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS-1 mutations must have progressed on standard treatment options including EGFR, ALK, or ROS-1-directed therapies.
Epidermal growth factor receptor (EGFR) mutant and/or anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearranged tumor
TREATMENT: Patients with non-small cell lung cancer (NSCLC) must have previously been tested for the presence of epidermal growth factor receptor (EGFR) mutations, and, if detected, should have received and progressed on EGFR tyrosine kinase inhibitor (TKI) therapy
Patients must have newly diagnosed histologically or cytologically confirmed NSCLC, staged IIIB or IV, for which they have not received first-line cytotoxic chemotherapy (first-line epidermal growth factor receptor [EGFR] inhibitors or anaplastic lymphoma kinase [ALK] inhibitors are allowed given disease progression)
Subjects should have received at least one prior platinum based chemotherapy and an immune checkpoint targeted agent; subjects with epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-translocated non-small cell lung cancer (NSCLC) should have received Food and Drug Administration (FDA)-approved targeted therapies as appropriate
Dose Expansion: Histologically confirmed and documented, previously untreated or treated stage IIIB or IV Non-Small Cell Lung Cancer (NSCLC) having failed no more than 1 previous platinum containing chemotherapy regimen for locally advanced or metastatic disease or relapsed/refractory locally advanced or metastatic gastric adenocarcinoma having failed no more than 2 previous chemotherapy regimen for locally advanced or metastatic disease. Subjects with NSCLC who are known to be epidermal growth factor receptor (EGFR)-mutation positive must have received an EGFR inhibitor and subjects known to be anaplastic lymphoma kinase (ALK)-mutation positive must have received an ALK inhibitor. Prior to enrollment, confirmation of the following must be obtained: • Dose expansion - For subjects in the dose expansion portion of the study, it is mandatory that available archived tumor tissue in FFPE block or minimum 10 unstained consecutive core biopsy slides from 1 archival block that meet specific tissue requirements are available.
Tumors with epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive treated with a tyrosine kinase inhibitor are permitted; however, subjects should have progressed on or be intolerant to the targeted therapy.
Non-small cell lung cancer (NSCLC)\r\n* Metastatic or locally advanced disease that progressed after at least one prior therapy \r\n* Note: patients who have actionable molecular targets (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ros oncogene 1[ROS1] mutations) must have received (when indicated) prior appropriate targeted therapy using Food and Drug Administration (FDA)-approved agents
Has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated.
Participants with epidermal growth factor receptor (EGFR) sensitizing mutations and anaplastic lymphoma kinase (ALK) rearrangements
Histological or cytological diagnosis of Stage IV NSCLC lacking epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation, and received no prior systemic chemotherapy treatment for their metastatic NSCLC
Subjects with non-squamous histology must be tested for Epithelial Growth Factor Receptor (EGFR) mutations (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution) and Anaplastic Lymphoma Kinase (ALK) rearrangement if tests have not been previously performed. Subjects with progressive disease during or after EGFR or ALK tyrosine kinase inhibitor (TKI) regimens are eligible. Subjects are eligible if genetic test results are indeterminate or if no tumor tissue is available or accessible for testing as long as they have received one prior systemic therapy
Patients with NSCLC and known anaplastic lymphoma kinase (ALK) translocations or epidermal growth factor receptor (EGFR) mutations who have not received prior treatment with ALK or EGFR inhibitor.
Subjects must have histologically confirmed, unresectable, locally advanced or metastatic pleural or peritoneal predominantly (>50% of tumor component) epithelial mesothelioma or nonsquamous non-small-cell lung cancer (NSCLC). Both chemotherapy-naive and previously treated subjects will be eligible; however, newly diagnosed NSCLC subjects eligible for FDA-approved therapies should have received the same before enrollment (e.g. subjects with epidermal growth factor receptor [EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should have received FDA-approved targeted therapies).
Participants with non-squamous histology has known or unknown sensitizing epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase positive (ALK) mutation. Note: Participants with squamous histology and unknown EGFR and ALK mutational status are eligible.
ELIGIBILITY FOR TREATMENT ON ARM 1: NSCLC patients with a mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) must have demonstrated progression or intolerance to at least one of the corresponding targeted therapies (for example erlotinib or crizotinib)
Patients receiving first-line erlotinib, crizotinib for epidermal growth factor receptor (EGFR) mutant-positive or echinoderm microtubule associated protein like 4 (EML4)-anaplastic lymphoma receptor tyrosine kinase (ALK) positive NSCLC will be excluded
Known anaplastic lymphoma kinase (ALK) translocations
PART A: Non-small cell lung cancer (NSCLC) with adenocarcinoma histology must have been previously tested for both epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements
Histologically- or cytologically-confirmed stage IV non-squamous, NSCLC who have progressed after at least one prior line of treatment; in the expansion phase, participants are only eligible if their molecular category has not been fully enrolled (10 participants with epidermal growth factor receptor (EGFR) mutations, 5 participants with anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement, 5 participants with wild type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), EGFR and ALK)
Progression following a single line of prior cytotoxic therapy including a platinum agent plus a standard cytotoxic partner other than a taxane (typically pemetrexed, gemcitabine or vinorelbine):\r\n* Previous treatment with targeted therapy will not count as a prior line of therapy if the patient’s tumor has the relevant molecular change (e.g., epidermal growth factor receptor [EGFR] mutation for erlotinib and echinoderm microtubule associated protein like 4 [EML4]/anaplastic lymphoma receptor tyrosine kinase [ALK] or receptor tyrosine kinase [ROS1] for crizotinib)\r\n* Previous treatment with immune-oncologic agents (such as nivolumab) will not count as a prior line of therapy
Tumors with driver mutations (epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive) should have had disease progression or been intolerant to the standard tyrosine-kinase inhibitor (TKI), and should include a second line TKI where such therapy is available and indicated.
Patients known to be positive for activating Epidermal Growth Factor Receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation
Persons with tumors known to have biomarkers predictive of resistance to erlotinib therapy (specifically Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, anaplastic lymphoma receptor tyrosine kinase [ALK] gene rearrangements, and EGFR T790M mutations) will be ineligible for study participation; if the results of molecular studies are not available or known at the time of study registration and subsequently become available, such participants will be considered eligible and if deriving clinical benefit may continue receiving erlotinib at the discretion of the investigator and study chair
Lung adenocarcinoma with an Anaplastic Lymphoma Kinase (ALK) gene rearrangement
Patients with known activating mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma receptor tyrosine kinase (ALK) or c-ros oncogene 1, receptor tyrosine kinase (ROS-1) (this test [ROS-1] will be done only on select patients and at the discretion of treating physicians) translocation positive; the mutational status of all patients will be determined prior to study entry
Tumor without activating driver mutations for which there is available therapy (eg, tumor without mutations in epidermal growth factor receptor or anaplastic lymphoma).
In countries where anaplastic lymphoma kinase (ALK) inhibitors are available for the treatment of NSCLC, subjects need to have been screened for ALK fusion gene rearrangements and excluded if positive, unless previously treated and progressed on an appropriate tyrosine kinase inhibitor (TKI) therapy
Patients with targetable mutation i.e. epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK), must have been treated with at least 1 prior tyrosine kinase inhibitor (TKI)
Patients must have received at least one platinum-containing regimen for the treatment of advanced or metastatic disease (except for epidermal growth factor receptor [EGFR]-mutant patients); prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen; NSCLC with documented EGFR mutation will be eligible after progression on an EGFR-tyrosine-kinase inhibitor (TKI) alone; NSCLC with other molecular targets, such as fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as echinoderm microtubule associated protein like 4 [EML4]-ALK) or ROS proto-oncogene 1 , receptor tyrosine kinase (ROS-1), will be eligible if they have progressed on targeted agents (ALK inhibitor) and chemotherapy or are not a candidate for chemotherapy
The institution’s pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known “sensitive” mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations
Anaplastic lymphoma kinase (ALK) translocations
LUNG ADENOCARCINOMA COHORT (COHORT 3 ONLY): Patients must have had at least one prior therapy for advanced disease (platinum-containing chemotherapy or one of the approved targeted therapies [an approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for EGFR mutant tumors or crizotinib and ceritinib for anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors]); there is no limit to the number of prior chemotherapy regimens received
Failed or were intolerant to at least one prior systemic treatment regimen with oral or IV medications and have no additional therapy options known to prolong survival with the exception of PD-1 or PD-L1 blockade therapy for subjects who will be enrolled in treatment arm A. Subjects with non-small cell lung cancer must have received at least one platinum doublet regimen. Subjects with known epidermal growth factor receptor tyrosine kinase inhibitor activating mutations or anaplastic lymphoma kinase rearrangement must have also exhausted approved targeted therapy options;
Known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutated disease (molecular testing not required prior to study entry)
There will be no limit on number of prior therapies for NSCLC; patients with previously untreated NSCLC will be eligible if they are uninterested in or ineligible for standard first line chemotherapy; patients with NSCLC known to harbor an anaplastic lymphoma kinase (ALK) rearrangement, or epidermal growth factor receptor (EGFR) mutation known to be sensitive to Food and Drug Administration (FDA) approved tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression (during or after treatment) or intolerance to an FDA approved EGFR TKI or ALK TKI, respectively
Subject with a tumor of non-squamous histology must be tested for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement. Subject with EGFR activating mutation or ALK rearrangement must have experienced disease progression or unacceptable toxicity/intolerance after receiving at least one EGFR tyrosine kinase inhibitor or ALK inhibitor;
Patients with epidermal growth factor receptor (EGFR) overactivity mutations or anaplastic lymphoma kinase (ALK) rearrangements must have received tyrosine-kinase inhibitor (TKI) therapy prior to consideration for enrollment;
Radiographic disease recurrence or progression during or after front-line platinum-based doublet chemotherapy. For patients with known epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) translocations, appropriate targeted treatment should have been used. Mutation testing is not required.
For participants with a documented epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, one additional line of non-cytotoxic prior treatment will be permitted provided the therapy is a targeted agent against the EGFR mutation or ALK rearrangement.
Presence of an activating EGFR (epidermal growth factor receptor) mutation or ALK (anaplastic lymphoma kinase) translocation in the tumor.
Known presence of documented sensitizing epidermal growth factor receptor (EGFR) activating mutation or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation (screening following local standards, but strongly encouraged in non-squamous histology)
Patients with any known epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma receptor tyrosine kinase (ALK) translocation
NSCLC with documented epidermal growth factor receptor (EGFR) mutation associated with response to EGFR inhibitors or documented fusion gene involving anaplastic lymphoma kinase (ALK) gene
Participants with sALCL must have documented anaplastic lymphoma kinase (ALK) status and must be beyond first remission or refractory to front-line chemotherapy
Documented anaplastic lymphoma kinase (ALK) status.
No prior treatment for Stage IV non-squamous or squamous NSCLC. Participant known to have a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded from the study
Participants with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic alternations should have PD on prior US-FDA approved therapy for these aberrations.