Lung cancer is the most common cancer and cause of cancer related mortality worldwide in 2018. In India, lung cancer is the 4^th most common cancer and third most common cause of cancer related mortality. Majority of the lung cancer presents in metastatic stage at presentation. The standard treatment for metastatic lung cancer was systemic chemotherapy. However, with the advent of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutation in patients with non-small cell lung cancer (NSCLC), the management of metastatic lung cancer underwent a paradigm shift in the last decade.

Tyrosine kinase inhibitor therapy against the EGFR mutations have shown a dramatic improvement in the progression free and overall survival of patients with metastatic lung cancer. Currently, the standard of care for metastatic NSCLC with EGFR mutations is EGFR tyrosine kinase inhibitors. EGFR sensitizing mutation are usually seen in Exon 18, 19, 20 and 21 with 19 and 21 being the most common and sensitizing mutations of EGFR domain. Gefitinib was the first generation TKI to show improvement in PFS in lung adenocarcinoma (1). Subsequently, several randomized and prospective studies have shown improvement in PFS and OS with second generation and third generation EGFR TKI(2–5).  Incidence of EGFR mutation is reported to be seen in 10-15% patients of European origin and 40-50% in East Asian population. The likelihood of EGFR mutations positivity is higher in female, non-smoker and East Asian populations.

The incidence of ALK mutation is approximately 3-5% in NSCLC patients(6). The probability of ALK mutations is also higher in younger, nonsmoker and population of East Asian descent. Crizotinib is an oral TKI against the ALK, ROS1 and Met mutations. Crizotinib have shown a considerable improvement in PFS as compared to systemic chemotherapy (10.9 vs 7.0 months, P= ) in the landmark study by Solomon et al (7). Similar to EGFR directed therapy with TKI, ALK inhibitors also showed similar overall response rate of 70-80%. Second generation ALK inhibitor have also shown statistically significant improvement in PFS as compared to systemic chemotherapy(8).

TKI therapy has resulted in median PFS ranging from 10-12 months(5,9–14) as compared to 4-5 months with standard platinum-based doublet chemotherapy. Majority of the patients would progress eventually within first year after starting treatment. This is due to acquired resistance to the TKI therapy. In EGFR driven lung cancer, the most common acquired resistance is through T790M point mutation in exon 20 of EGFR gene(15).  Resistance to ALK targeted treatment also develop through a variety of mechanisms including ALK mutations, however precise mechanisms is being understood. After progression, second line EGFR or ALK inhibitors are the treatment of choice.  The progression could be widespread and symptomatic or at few original sites of gross disease called as oligo progression. In the former scenario, treatment with subsequent generation TKI or alternatively systemic chemotherapy is an option depending upon patient performance status, disease free interval and results of repeat biopsy. In the oligo progression setting, which is seen in approximately 20 - 45% of progressive disease after TKI, consolidative therapy to the oligo progressive sites by radiation or surgery has resulted in improved local control rates(16–18). In matched cohort analysis by Chan et al, comparing local RT and chemotherapy after oligo progression, median OS was significantly improved with RT than CT (28.2 vs 14.7 months, p=0.026)

Another option is to treat the oligo metastatic sites before progression sets in and further prolong the progression free interval. This is possible as in majority of patients the original site of disease will be the ones progressing on TKI and with local consolidative radiation therapy (LCRT), there is a good possibility to prevent oligo progression. In addition, ablative doses to residual disease sites could reduce the chances of metastatic reseeding at distant sites.

In oligo metastatic NSCLC with less than 3-5 metastatic disease sites at presentation, two recently concluded phase II randomized controlled trial have shown a dramatic improvement in progression free survival with the addition of local consolidative therapy after initial standard therapy as compared to maintenance treatment alone(19,20).  Gomez et al has shown that the addition of local consolidative therapy to 1-3 oligo metastatic sites in NSCLC has improved PFS (11.9 vs 3.9 months, p=0.005)(20). Palma et al also compared stereotactic ablative body radiotherapy (SABR) in addition to standard of care versus standard of care alone in 1-5 metastatic sites from different primary tumors and demonstrated improvement in overall survival. In subgroup analysis limited to lung primary, improvement in overall survival with SABR was maintained.  There are various other studies, which have shown that local radiation therapy in addition to the standard systemic treatment showed a greater benefit when compared to systemic treatment alone(21). Local radiation therapy with higher doses per fraction also stimulates a systemic immune response and release tumor associated antigens. Another hypothesis is the abscopal effects of local radiotherapy.

In oligo metastatic NSCLC patients with positive oncogene mutations, addition of local consolidative RT to the oligo metastatic sites improves progression free survival as compared to continuation of TKI alone. Median progression free survival in EGFR and ALK positive patients is in the range of 10-12 months. Local consolidative radiation therapy after 3 months of TKI without progressive disease to limited sites of metastases [1-5 sites] will improve PFS and overall survival as compared to continuation of TKI alone.  There are at least two retrospective studies, which have evaluated the role of local consolidative therapy (LCT) in addition to TKI alone. Hu et al evaluated 231 pts of oligo metastatic lung adenocarcinoma who received TKI alone or TKI plus LCT and have shown improvement in PFS from 10 to 15 months (HR – 0.6, p=0.000) (22). Xu et al evaluated 145 patients of oligometasatic disease with EGFR mutations treated with TKI alone and local consolidation therapy in the form of radiotherapy, surgery or both. They found that patients who have received LCT to all sites including primary disease have a better PFS than those who do not received any LCT (20.6 months vs 13.9 months, p<0.001). The role of local consolidative radiation therapy in a randomized setting is available in literature in oligo metastatic NSCLC but not in a selective population like oncogene mutated NSCLC. Hence, we propose a phase II randomized controlled trial between TKI alone and TKI plus local consolidative SBRT to 1-5 sites of oligo metastatic NSCLC with EGFR and ALK mutations.

Randomization Arms: Eligible patients will be randomized in 1:1 ratio to TKI alone or TKI + LCRT. This will be an intention to treat randomized study.

Arm 1: Continuation of TKI therapy alone

Arm 2:  Continuation of TKI therapy + Local Consolidative Radiation therapy to 1-5 sites