Addition of consolidative radiation therapy to TKI versus TKI alone in driver mutated lung cancer patients

Phase 2

Recruiting

• Conditions: Malignant neoplasm of unspecifiedpart of bronchus or lung,

• Registration Number: CTRI/2019/11/021872
• Lead Sponsor: Tata Memorial Hospital

Brief Summary

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

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

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

TKI therapy has resulted in median PFS ranging from 10-12months(5,9–14) as compared to 4-5 months withstandard platinum-based doublet chemotherapy. Majority of the patients wouldprogress eventually within first year after starting treatment. This is due toacquired resistance to the TKI therapy. In EGFR driven lung cancer, the mostcommon acquired resistance is through T790M point mutation in exon 20 of EGFRgene(15). Resistance to ALK targeted treatment also develop through a variety ofmechanisms including ALK mutations, however precise mechanisms is beingunderstood. After progression, second line EGFR or ALK inhibitors are thetreatment of choice.  The progressioncould be widespread and symptomatic or at few original sites of gross diseasecalled as oligo progression. In the former scenario, treatment with subsequentgeneration TKI or alternatively systemic chemotherapy is an option dependingupon patient performance status, disease free interval and results of repeatbiopsy. In the oligo progression setting, which is seen in approximately 20 -45% of progressive disease after TKI, consolidative therapy to the oligoprogressive sites by radiation or surgery has resulted in improved local controlrates(16–18). In matched cohort analysis by Chanet al, comparing local RT and chemotherapy after oligo progression, median OSwas significantly improved with RT than CT (28.2 vs 14.7 months, p=0.026)

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

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

In oligo metastatic NSCLC patients with positive oncogenemutations, addition of local consolidative RT to the oligo metastatic sites improvesprogression free survival as compared to continuation of TKI alone. Medianprogression free survival in EGFR and ALK positive patients is in the range of10-12 months. Local consolidative radiation therapy after 3 months of TKI withoutprogressive disease to limited sites of metastases [1-5 sites] will improve PFSand 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 additionto TKI alone. Hu et al evaluated 231 pts of oligo metastatic lung adenocarcinomawho received TKI alone or TKI plus LCT and have shown improvement in PFS from10 to 15 months (HR – 0.6, p=0.000) (22). Xu et al evaluated 145 patients ofoligometasatic disease with EGFR mutations treated with TKI alone and localconsolidation therapy in the form of radiotherapy, surgery or both. They foundthat patients who have received LCT to all sites including primary disease havea better PFS than those who do not received any LCT (20.6 months vs 13.9months, p<0.001). The role of local consolidative radiation therapy in arandomized setting is available in literature in oligo metastatic NSCLC but notin a selective population like oncogene mutated NSCLC. Hence, we propose aphase II randomized controlled trial between TKI alone and TKI plus localconsolidative SBRT to 1-5 sites of oligo metastatic NSCLC with EGFR and ALKmutations.

**Randomization Arms:** Eligible patients will be randomized in 1:1 ratio toTKI 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

Detailed Description

Not available

Study Timeline

• Study Start: 2019-11-11
• Last Update Posted: 2022-01-02

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 106

Inclusion Criteria

1)Patients with pathologically proven diagnosis of NSCLC 2)Patients with positive oncogene driver mutation (EGFR or ALK/ROS) 3)Patients who have received at least 2-4 months of TKI therapy without progression 4)Patients with 1-5 sites of metastatic disease not including the primary tumor and regional nodes (less than 3 metastatic lesions in one organ will be eligible and 4 or more metastatic lesions in one organ will be ineligible) 5)Patients suitable for local consolidative therapy 6)Adequate end organ function CBC/differential obtained within 15 days prior to registration on study, with adequate bone marrow function defined as follows: •Absolute neutrophil count (ANC) ≥ 500 cells/mm3; •Platelets ≥ 50,000 cells/mm3; •Hemoglobin ≥ 8.0 g/dl (Use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable); 7)Patients with ECOG performance status of 0-2 8)Age > 18 years 9)For females of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to study registration;.

Exclusion Criteria

1)Patients with progressive disease after 2-3 months of initial TKI therapy 2)Patients with negative oncogene driver mutations (EGFR/ALK/ROS) 3)Patients not suitable for local consolidative radiation therapy 4)Patients who are not suitable for further continuation of TKI therapy due to toxicity 5)Severe, active co-morbidity defined as follows: •Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; •Transmural myocardial infarction within the last 6 months; •Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; 6)Patients with prior history of radiation therapy to thorax 7)Patients with second malignancy (Synchronous or Metachronous) 8)Pregnancy.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To determine progression free survival	Median

Secondary Outcome Measures

Name	Time	Method
1)To determine overall survival	2)To evaluate local control rates of oligometastatic sites

Trial Locations

Locations (1)

Tata Memorial Hospital; 🇮🇳 Mumbai, MAHARASHTRA, India

Tata Memorial Hospital

🇮🇳Mumbai, MAHARASHTRA, India

Anil Tibdewal

Principal investigator

022-24177000

aniltibdewal@gmail.com