Re-induction of a systemic immune response after initial response with immune therapy with radiotherapy in metastatic or locally recurrent lung cancer

Immune therapy with checkpoint inhibitors have changed the outcome of patients
with metastatic non-small cell lung cancer (NSCLC) in first and in second line,
with improved progression-free survival (PFS), overall survival (OS) and
quality of life compared to standard chemotherapy. Inhibitors of the PD-1/
PD-L1 axis are now approved for the treatment of patients with metastatic NSCLC
in first line or second line treatment.
Radiation has consistently been shown to activate key elements of the immune
system. Radiotherapy in combination with different forms of immune therapy such
as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and
Toll-like receptor agonists improved consistently local tumor control and very
interestingly, lead to better systemic tumor control (the *abscopal* effect)
and the induction of specific anti-cancer immunity with a memory effect.
Moreover, as PD1/PD-L1 is upregulated by radiation and radiation can overcome
resistance for PD-(L)1 blockage, their combination is logical.
In small series, it has been shown that a new long-lasting remission can be
induced by irradiating one tumor site in patients who showed cancer progression
after an initial response to immune therapy alone or concurrent immune therapy
and chemotherapy . In these series, the original immune therapy was continued
and the treatment was very well tolerated.

To investigate the progression-free survival after radiotherapy to a single
lesion in patients with stage IV non-small cell lung cancer who achieved at
least stable disease with immune therapy alone or concurrent immune therapy and
chemotherapy and who show disease progression. The same immune therapy will be
continued.

This is a prospective, single arm phase II trial.

Patients continue the same immune therapy they already received and get
radiotherapy to one lesion. The lesion may or may not be symptomatic. The
preferred radiotherapy dose is 24 Gy in 3 fractions (dosage on the 10 Gy
isodose is allowed), but other fractionation schedules (e.g. 30 Gy/ 10
fractions, 20 Gy/ 5 fractions, 20-24 Gy / 1 fraction for SRS) are allowed if
these are standard for a certain location or palliative indication in the body.

The patients will have some toxicity of radiotherapy. This will be dependent on
the dose and of the location of the tumour. However, the radiotherapy is with
the exception of stereotactic radiosurgery (SRS) for brain metastases, low dose
palliative doses, of which only low to moderate side effects are expected. For
SRS, this will be a standard indication because of symptomatic brain metastases
progression. The latter patients would receive the same SRS anyway. The
combination of radiotherapy with the checkpoint inhibitors that are used for
lung cancer have been investigated in several trials, and no additional
toxicity above the two treatment modalities alone has been reported. The risks
and side effects of the blood withdrawals (4x) are negligible.