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Lung cancer, one of the most frequently diagnosed cancers worldwide has long relied on testing for the molecular biomarkers EGFR/ALK. However, achieving superior clinical outcomes for patients with lung cancer requires developing comprehensive techniques beyond contemporary EGFR/ALK testing. Current technologies are on par with molecular testing for EGFR/ALK in terms of efficacy, most of them failing to offer improvements perhaps primarily due to skepticism among clinicians, despite being recommended in the NCCN guidelines. The present study endeavored to minimize chemotherapy-dependence in EGFR/ALK-negative patient cohorts, and use evidence-based methods to identify ways to improve clinical outcomes. In total, 137 lung cancer cases obtained from 'PositiveSelect NGS data', comprising 91 males and 46 females, were investigated. EGFR- and ALK-positivity was used for data dichotomization to understand the therapeutic utility of rare gene alterations beyond just EGFR/ALK. Statistics obtained from PositiveSelect were collated with data from international studies to construct a meta-analysis intended to achieve better clinical outcomes. Upon dichotomization, 23% of cases harbored EGFR variants indicating that treating with EGFR TKIs would be beneficial; the remaining 77% exhibited no EGFR variants that would indicate favorable results using specific currently available chemotherapy practices. Similarly, 28% of cases had EGFR+ALK variants favoring EGFR/ALK-based targeted therapeutics; the remaining 72% harbored no EGFR/ALK variants with known beneficial chemotherapy routes. The present study aimed to overcome current inadequacies of targeted therapies in patients with a conventional EGFR/ALK-positive diagnosis and those in EGFR+ALK-negative cohorts. Upon analysis of the negative cohorts, significant and clinically relevant single nucleotide variants were identified in KRAS, ERBB2, MET and RET, with frequencies of 7, 1, 2 and 3% in patients who were EGFR-negative and 6, 1, 1, and 3% in patients who were EGFR and ALK-negative, respectively, enabling the use of targeted therapeutics aside from EGFR/ALK TKIs. From the results of the current study only 35% of the two negative arms (EGFR negative and EGFR+ALK negative) would be recommended NCCN or off-label chemotherapy; prior to the current study, the entire cohorts would have been recommended this treatment. The present study emphasizes the potential of comprehensive genomics in identifying hallmarks of lung cancer beyond EGFR/ALK, using broad-spectrum genetic testing and data-sharing among medical professionals to circumvent ineffective chemotherapy.