This study aims to determine if it is feasible to collect samples of blood and viable lung cancer tissue in patients with either:

• Stage IV mutation-driven NSCLC
• Stage II-III NSCLC undergoing neoadjuvant immunotherapy prior to surgery

Viable tissue has been defined by the collaborating pathology department as the presence of viable tumour cells, in accordance with recommendations from the International Association or the Study of Lung Cancer.

In patients with stage IV NSCLC, obtaining adequate samples of viable tissue for advanced testing can be challenging, as sites of cancer that are accessible by biopsy are often small, and contain few viable cancer cells. If obtained, however, viable blood and tissue specimens can be utilised for genetic and other analyses aimed at identifying cancer markers that may offer prognostic information, or that may potentially lead to development of therapies that target these markers in the future.

In patients with stage II-III NSCLC, the use of immunotherapy prior to surgery has been shown to affect the proportion of viable tumour tissue at the time of surgery, although this needs to be further studied. There is a need to better understand the genetic basis of these tumours to improve response rates to immunotherapy prior to surgery.

The study will be open for four years in total. The first three years will consist of recruitment and participant follow up, and the fourth year will consist of follow up only. Data analysis will occur in the fifth year when the study is closed.

Rationale Benchmarking the proportion of patients who are able to provide paired samples of blood and viable tumour tissue is important in oncogene-addicted metastatic NSCLC patients as investigators have now entered the era of genotype-guided post-progression targeted therapies. In the early-stage operable NSCLC context, benchmarking the feasibility of paired samples is of interest as neoadjuvant CPI-based therapy has recently emerged as a new standard of care strategy.

As such, investigators have defined the following cohorts within our study:

Cohort 1: Oncogene-addicted NSCLC, due to commence new line of targeted therapy

• Sub-cohort 1A: treatment naïve, oncogene-addicted NSCLC
• Sub-cohort 1B: pre-treated, oncogene-addicted NSCLC, received prior targeted therapy
• Sub-cohort 1C: pre-treated, oncogene-addicted NSCLC, no prior targeted therapy (can have received chemotherapy/CPI/chemo-CPI) Cohort 2: Early-stage operable NSCLC undergoing neoadjuvant CPI therapy

Primary aim

To estimate the feasibility of collecting paired samples of blood and viable tissue in patients with:

• Oncogene-addicted metastatic NSCLC commencing new line of targeted therapy at progression (Cohort 1), and
• Early-stage operable NSCLC undergoing neoadjuvant CPI-based therapy (Cohort 2) Viable tissue is defined by the presence of viable tumour cells. Viable tumour cells are defined by those with well-preserved architectural and cytological features, in line with the latest recommendation from the International Association for the Study of Lung Cancer (IASLC), evaluated by a specialist pulmonary pathologist using a haematoxylin & eosin (H&E) stained slide.

Secondary aims

To estimate the feasibility of obtaining viable tissue samples at:

• Baseline (sub-cohort 1B)
• PD (Cohort 1)
• Surgery (Cohort 2)

Exploratory aims

• To identify genes/proteins associated with disease progression on targeted therapy (Cohort 1)
• To measure levels of tumour cell-recognising antibodies in patients on targeted therapy (Cohort 1)
• To identify genes/proteins associated with tumour regression (Cohort 2)

Inclusion Criteria (Cohort 1):

1. Age >/= 18.

2. Histologically confirmed locally advanced or metastatic NSCLC

3. ECOG performance score 0-2

4. Tier 1 ASCO/AMP NSCLC oncogenic variant identified through routine clinical methods, e.g. EGFR, ALK, ROS1, RET, MET, KRAS, BRAF, HER2, NTRK

5. Planned to commence targeted therapy (any line of therapy)

   o This includes bispecific antibodies (e.g. amivantamab), and antibody-drug conjugates (e.g. trastuzumab-deruxtecan)

6. Regular follow-up and monitoring for cancer recurrence per standard of care planned at the enrolling site

7. Provided written informed consent to participate in the study

Inclusion Criteria (Cohort 2)

1. Age >/= 18.
2. Histologically confirmed stage II/III operable NSCLC
3. Planned to undergo neoadjuvant CPI-based therapy
4. Provided written informed consent to participate in the study

Exclusion Criteria:

• Patient too medically unstable to commit to sampling required for the study

The Royal Marsden NHS Foundation patients