Studies

• Has LS-SCLC, defined as Stage I-III (T any, N any, M0) that can be safely treated with twice-daily RT [45 Gy in 30 twice-daily fractions over 3 weeks], or once-daily RT [60 Gy to 66 Gy in 33 daily fractions over 6 weeks]). 
• Has not received prior treatment (chemotherapy or radiotherapy or surgery resection)l for LS SCLC
• Has adequate PFT defined as an FEV1 >50% of predicted normal volume and a DLCO >40% of predicted normal value. 
• Clearance of 50ml/min
• Submit pretreatment tumor tissue sample or cytologic sample

• histologically or cytologically confirmed ES-SCLC and no prior systemic treatment for ES-SCLC 
• Subjects with prior treatment for limited-stage SCLC (LS-SCLC) are permitted 
• Parts 1 to 4 and 7: Subject must have received 1 cycle of platinum chemotherapy, etoposide, and PD-L1 inhibitor.  
• Parts 5, 6, 8, and 9: Subjects must have completed 4 cycles of first-line platinum chemotherapy, etoposide, and PD-L1 inhibitor and not have experienced disease progression. 

• progressieve SCLC ES/LS 
  • progression following or during 1line plat based systemic chemo for LS or ES
  • patients who received treatment for LS disease who recur are eligible
  • first line chemo+PDL1inh: patient should have failed on PDL1inh
• central tissue evaluation (cyto/histo) 

• Patients should have resectable (Stage II to Stage IIIA disease.For subjects with N2 disease, only those with 1 single nodal station ≤ 3 cm are eligible) and be candidate for lobectomy, sleeve resection, or bilobectomy at the time of screening
• No prior exposure to immune-mediated therapy
• excl: Patients who require preoperative radiotherapy treatment as part of their care plan.
• Testing for EGFR/ALK is mandatory for subjects with adenocarcinoma or never smokers with squamous histology
• Availability of pretreatment tumor tissue biopsy 

• Stage IV first line setting with TPS≥50% planned to receive anti-PD1 monotherapy, 
• Exclusiecriteria: 
  • Rt for stage IV except palliative radiotherapy, : 1week washout
  • active brain meta’s: 2weeks washout RT+ cortico
  • patient presents at screening anti-HLA antibodies against HLA molecules expressed by the PDC*line., 
  • mixed tumor, mutated
  • Lymfocyts below 1x10 9de/L
  • splenectomy
  • infarct within 6 months
     

• Have an ECOG performance status of 0-1
• Have a histologic confirmation of metastatic NSCLC of squamous (SQ) or non-squamous (NSQ) histology with Stage IV A/B or recurrent disease
• No prior systemic anti-cancer treatment (including EGFR, ROS-1, and ALK inhibitors) given for primary therapy for advanced or metastatic disease
• Prior definitive chemoradiation/chemo for locally advanced or ES LC: at least 6 months prior to enrollment. 
• Central PDL1 testing on tissue ( ebus ok): 10days turnaround for result
   

• pathologically or cytologically confirmed Stage IV NSCLC who could be treated with pembrolizumab alone or combined with carboplatin/pemetrexed or paclitaxel
• patients having undergone pneumonectomy or bilobectomy (except if bilobectomy includes the right middle lobe) are excluded
• The patient must have a resting oxygen saturation of at least 90%, a FEV1 ≥50% of predicted values as determined by spirometry and a DLCO of at least 50%.
• Patients with a known history or current evidence of any chronic upper or lower respiratory conditions are excluded
• Patients with previous history of malignancy provided that patient has been free of disease for at least 3 years may be included.
• Patients with a known history of a thromboembolic event  within 3 months prior to n (D1). are excluded
• Patients with a known history of any of the following conditions: presyncope or syncope of either unexplained or cardiovascular etiology, uncontrolled ventricular arrhythmia are excluded
• creatinine clearance >60 mL/min

• NSCLC starting with immunotherapy, no corticosteroid use above 8mg/d is allowed

• Histologically or cytologically  NSCLC stage IIIB-IV
• Documented tumour cell PD-L1 status as assessed by a central laboratory: 
• Documented radiological PD whilst on or after receiving the most recent treatment regimen.
• must have received an anti-PD-(L)1 therapy and a platinum doublet containing therapy for locally advanced or metastatic NSCLC either separately or in combination. Prior durvalumab is acceptable. 
• Received a minimum of 8 weeks of an anti-PD-(L)1 and at least 2 cycles of platinum-doublet containing regimen for locally advanced or metastatic NSCLC (either separately or in combination).
• Radiotherapy: ≥ 4 weeks 
• Documented EGFR and ALK wild-type status as determined at a local laboratory (SQ and NSQ)

• Metastatic non-squamous NSCLC patients who have been treated with IO or IO/IO combination only (no chemotherapy) in the metastatic 1L setting and progressed on or after at least 12weeks of anti-PDL1 treatment OR Stage 3 non-squamous unresectable NSCLC patients post Chemoradiotherapy who have been treated with durvalumab and progressed after at least 6 months of treatment. 
• Can provide existing biopsy taken within 2 years prior to entering trial 
   

• Histologically or cytologically documented NSCLC adenocarcinoma presenting with metastatic disease 
• progressed during/after prior approved therapies (i.e. platinum-doublet chemotherapy and anti-PD-1/PD-L1 given either concurrently or sequentially in the metastatic setting or target therapy in participants with oncogenic driver mutation
• no more than 2 prior lines of therapy in the metastatic setting (no more than 1 prior line of chemotherapy),  In participants with approved target therapy for oncogenic driver mutations up to 3 lines are allowed
• Radiologically documented disease progression during or after last treatment
• Blood/platelet transfusion, hematopoietic stimulating agent including granulocyte colony stimulating factor (G-CSF) formulation ≥ 1 week

• Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third-generation EGFR TKI. If a subject has received 2 prior lines of EGRF TKI therapy, administration of the third-generation EGRF TKI must have been in the most recent line and in the setting of NSCLC with a demonstrated T790M substitution
• Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI
• Documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R.
• Archival/new tumor tissue collected from a biopsy performed on or after treatment with most recent TKI 
• CrCl ≥45 mL/min

• Must have at least one documented sensitising EGFR mutation: exon19 deletion, L858R mutation, and/or T790M.
• EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on first- or second-line treatment with osimertinib as the most recent therapy
• Participants must be chemotherapy and immunotherapy (i.e., PD-1 inhibitor, PD-L1 inhibitor, T-lymphocyte-associated protein 4 inhibitor) naïve in the metastatic setting
• clearance ≥ 45 mL/min

• Established histological diagnosis of advanced NSCLC, not suitable for radical treatment, + EGFR actionable mutation receiving first-line targeted TKI therapy with osimertinib
• Initial radiologically confirmed response (at least stable disease) to osimertinib assessed 3 months post commencing osimertinib according to RECIST criteria v1.1.
• Confirmed PD defined as ≤ 3 intra- and extracranial sites of progressive disease

• NSCLC stage IIIB-IV+ EGFR or HER mutation
• Documented disease progression after treatment with at least one prior systemic therapy for advanced disease. Participants who do not have standard of care access due to any reason, are intolerant to, or are not eligible for standard treatments, may also be eligible. Participants previously treated with systemic therapy who are known to have acquired an actionable resistance alteration in a gene other than EGFR/HER2 should first be treated with available approved therapy that targets the identified gene alteration prior to enrolling to this study
• Adequate archival tumor tissue (ideally taken after last targeted treatment and not older than 6 months) has to be available, either from primary or metastatic sites. If archival material is not available, a fresh tumor biopsy should be performed if feasible and if the procedure poses no significant risk for the participant
• eGFR) > 60 mL/min

NSCLC stage IIIB-IV+ EGFR or HER mutation

• NSCLC starting with immunotherapy, no corticosteroid use above 8mg/d is allowed

• availability of t umor tissue 
• Part 1 only: NSCLC, who have progressed on standard of care therapy and are not amenable to surgical resection or other approved therapeutic options t
• Part 2 only: Subjects with advanced c-Met overexpressing non-squamous or squamous NSCLC as assessed by a central laboratory
• This includes subjects who have progressed after treatment with at least: 
• Platinum-based chemotherapy and an immune checkpoint inhibitor or appropriate targeted therapy, 
• Parts 2a: c-Met intermediate/high non-squamous wtEGFR NSCLC
• 2b mutated EGFR-expression (mutEGFR NSCLC)
• 2c: c-Met low non-squamous wtEGFR NSCLC
• 2d: c-Met overexpressing squamous NSCLC
   

• Cohort A: subjects whose tumors harbor a KRAS G12C mutation and a low (<1%)PD-L1 expression.
• Cohort B: subjects whose tumors harbor a KRAS G12C mutation, a positive (≥1%)PD-L1 expression and a STK11 co-mutation
• histologically confirmed locally advanced (stage IIIb/IIIc ineligible for definitive chemoradiation or surgery) or metastatic (stage IV) NSCLC subjects without previous systemic treatment for metastatic disease. Prior treatment with (neo)adjuvant platinum-doublet chemotherapy and/or an immune checkpoint inhibitor administered before and/or after surgery or concomitantly/sequentially with radiation therapy with recurrence after 12 months of therapy completion is allowed. 
• Presence of a KRAS G12C mutation determined by local testing ( or centrally at a Novartis designated laboratory prior to enrolment
• Mandatory provision of a FFPE tumor tissue sample for central evaluation

• Histologically confirmed diagnosis of NSCLC with KRASG12C mutation
• Receipt of prior treatment with a platinum (cisplatin or carboplatin)-containing regimen and an immune checkpoint inhibitor (i.e., anti-PD-1/PD-L1 inhibitor) concurrently or sequentially for advanced or metastatic disease with the outcome of objective disease progression on or after treatment
• Metastatic disease
• Prior treatment with an agent targeting KRAS G12C  is not allowed
• Expected availability of representative tumor specimen (primary or metastatic, archival or newly obtained) for central laboratory testing of KRAS G12C mutation status and correlative gene alterations (minimum of 7 slides, preferably 15 slides).
   

• Must have histologically confirmed Stage IB, II, or IIIA NSCLC
• Must have an activating RET gene fusion in tumor PCR or NGS
• Must have received definitive locoregional therapy with curative intent (surgery or radiotherapy) for Stage IB, II, or IIIA NSCLC. Receipt of prior systemic anti anti-cancer therapy is allowed but not required.