Treatments for lung cancer have advanced significantly over the last 2 decades, improving survival and long-term outcomes. However, lung cancer mortality remains high, and cures for metastatic disease have remained elusive. Here, we outline recent advances in our understanding of lung cancer biology and areas of interest for future therapeutic development, with a focus on resistance mechanisms, tumor heterogeneity, plasticity, minimal residual disease, and the tumor microenvironment. A comprehensive understanding of how these areas influence tumor biology will be essential for the development of future lung cancer therapies and to improve the care of lung cancer patients.

Brain metastases are a common complication among patients with non-small cell lung cancer and are historically associated with significant morbidity and limited survival. Although surgery and radiation therapy remain essential pillars in the clinical management of brain metastases, the development of several pharmacologic agents with activity in the central nervous system has broadened the role of systemic therapies for treating brain metastases. There is accumulating evidence that, in the appropriate clinical scenarios, systemic therapies may be used to manage both intracranial and extracranial disease while delaying local therapy and mitigating potential treatment-related morbidity. Determining the optimal treatment approach requires careful consideration of the intracranial tumor burden, location of lesions, pathologic and molecular profile, local and systemic therapy options, and overall prognosis. This review will provide updates on the medical management of non-small cell lung cancer brain metastases, with a focus on recent advances in systemic therapy options.

Unresectable, locally advanced nonsmall cell lung cancer (LA‑NSCLC) accounts for ∼20% to 30% of newly diagnosed cases of NSCLC and remains associated with poor long‑term outcomes. Concurrent chemoradiotherapy (cCRT) has long been the therapeutic backbone for unresectable stage III disease, and the addition of consolidative durvalumab represents a major advance, significantly improving progression‑free and overall survival. Nonetheless, early progression and treatment‑related toxicity limit benefit for many patients, prompting investigation into alternative immunotherapy sequencing and escalation strategies. To date, randomized trials evaluating concurrent immune checkpoint blockade or intensified consolidation have not demonstrated additional survival benefit. In contrast, emerging precision‑medicine approaches-including consolidative targeted therapy for oncogene‑driven tumors-have yielded profound improvements in selected populations. Concurrently, advances in radiation delivery emphasize individualized strategies to optimize local control while minimizing toxicity. This review summarizes evolving systemic and radiation‑based approaches for LA‑NSCLC, highlighting current limitations and future directions to improve outcomes.

Neoadjuvant and perioperative chemoimmunotherapy has transformed the treatment of tumors >4 cm or node-positive disease (stage II to IIIA, AJCC 8th edition) in non-small cell lung cancer (NSCLC). Compared with neoadjuvant chemotherapy alone, the addition of neoadjuvant immunotherapy to chemotherapy before resection has demonstrated improved pathologic complete response rate, event-free survival, and overall survival in stage II to IIIA NSCLC. The benefit observed with pathologic response after neoadjuvant therapy expands to include patients with stage II to IIIB NSCLC with sensitizing EGFR mutations with neoadjuvant osimertinib and is being evaluated with targeted therapies in additional actionable genomic drivers. Predictive biomarkers for pathologic response after neoadjuvant or perioperative therapies and biomarkers for disease recurrence, including evaluation of minimal residual disease through liquid biopsies, are under investigation to identify NSCLC patients who may have long-term survival with neoadjuvant or perioperative treatment. This chapter summarizes the current clinical landscape of neoadjuvant, perioperative, and adjuvant therapies and updates on surgical techniques for early-stage NSCLC.

Testing for predictive biomarkers in lung cancer has evolved to integrate immunohistochemistry, tissue-based next-generation sequencing (NGS), and liquid biopsy. Tissue-based NGS remains the foundation for comprehensive genomic profiling, enabling detection of actionable mutations and guiding personalized therapies. RNA-based assays complement DNA testing by improving fusion detection. Liquid biopsy using circulating tumor DNA (ctDNA) offers a minimally invasive alternative for genotyping, monitoring treatment response, and assessing minimal residual disease, though sensitivity challenges persist in early-stage disease. Immunohistochemistry for PD-L1 and emerging antibody-drug conjugate targets further expands therapeutic options. Workflow optimization, including molecular tumor boards, reflex testing, and rapid assays, is critical to reduce turnaround times. Lastly, advances in digital pathology and AI promise novel biomarker discovery and integration into clinical practice, ensuring accurate interpretation and personalized treatment strategies in the rapidly evolving field of lung cancer personalized oncology.

The introduction of immune checkpoint inhibitors targeting the programmed death-1 (PD-1) axis represented a major therapeutic advance, enabling long-term survival, and even cure, in a subset of patients, an outcome previously considered unattainable in metastatic disease. However, most patients do not yet derive sustained benefit. Despite extensive efforts to define biomarkers, identify mechanisms of sensitivity and resistance, and translate these insights into therapeutic strategies, attempts to intensify PD-1-based therapy have failed to improve long-term survival. Extending durable benefit and achieving cure in a broader population will require a deeper understanding of mechanisms of resistance, the development of novel immunotherapeutics, and more precise personalization of treatment strategies.

Oncogenic gene fusions define a clinically important subset of non-small cell lung carcinoma (NSCLC) for which targeted therapies have transformed outcomes. Over the past 15 years, successive generations of tyrosine kinase inhibitors (and more recently, monoclonal antibodies) have demonstrated substantial improvements in response rates, progression-free survival, and central nervous system control across multiple fusion-defined populations. This review consolidates current evidence for FDA-approved therapies targeting ALK, ROS1, RET, NTRK, and NRG1 fusions in lung cancer, highlighting mechanisms of action, pivotal clinical trials, resistance patterns, and toxicity profiles. We also discuss advances in molecular diagnostics (including the growing role of RNA-based sequencing) and emerging strategies in the adjuvant and perioperative settings. Finally, we outline ongoing clinical trials and future directions aimed at overcoming resistance and expanding precision oncology approaches for patients with rare fusion-driven lung cancers.

KRAS driver mutations have classically been considered undruggable by direct inhibitors in non-small cell lung cancer (NSCLC) as well as other solid tumors. However, recent advances have led to the first successful direct KRAS inhibitors, beginning with the development of KRASG12C inhibitors targeting the inactive GDP-bound state of KRAS. These initial KRASG12C (OFF) inhibitors demonstrated real but modest activity in KRASG12C-mutated mNSCLC. The development of more potent optimized KRASG12C (OFF) inhibitors has sought to improve upon the clinical activity of the initial raft of KRASG12C (OFF) inhibitors. Combination therapy with PD-1 inhibitors, as well as other classes of drugs, is also under intense investigation in NSCLC and other solid tumors. Nevertheless, primary and acquired resistance, as well as a variable and peculiar tendency to autoimmune hepatitis, have complicated efforts to develop this class of inhibitors in KRASG12C-mutated mNSCLC. In parallel, new direct inhibitor classes have emerged recently, including tri-complex ON-state inhibitors and dual-state ON/OFF inhibitors capable of targeting not only KRASG12C but also other KRAS mutations, as well as panKRAS and panRAS strategies. These agents have the potential to broaden the activity of initial KRASG12C (OFF) inhibitors and to avoid certain mechanisms of resistance and toxicity, but remain early in development with limited data. The KRAS therapeutic landscape is evolving rapidly, with many promising competing strategies each seeking to distinguish itself in an increasingly crowded therapeutic landscape.

Non-small-cell lung cancer (NSCLC) has seen a paradigm shift over the past quarter century driven by systematic molecular characterization, the advent of targeted therapies, the implementation of low-dose CT screening, and the integration of immunotherapy across the disease continuum. Genomic profiling has defined oncogene-addicted subsets for which targeted agents now improve survival in both metastatic and resectable disease, while immune checkpoint inhibitors have displaced chemotherapy as first-line treatment for many patients without actionable drivers and have been incorporated into perioperative and consolidation strategies. Concurrently, adjuvant and consolidation tyrosine kinase inhibition has extended precision oncology into early-stage EGFR- and ALK-driven NSCLC. Here, we review pivotal therapeutic advances across metastatic, locally advanced, and early-stage disease; identify the need for more discriminating markers to refine treatment intensity and sequencing; and outline emerging approaches, including rational upfront combinations and the use of circulating tumor DNA to enable real-time, adaptive modulation of therapy in NSCLC.

Emerging treatment paradigms in classic Hodgkin lymphoma (cHL), which increasingly incorporate immunotherapy and response-adapted strategies, have increased the need for more accurate disease assessment tools. PET/CT remains the cornerstone for staging and response evaluation, but has limited sensitivity for low-volume residual disease, interobserver variability, and a high false-positive in the setting of immunotherapy. Baseline clinical scores and erythrocyte sedimentation rate (ESR) provide baseline prognostic information but offer little insight into tumor biology or treatment response. Further, tissue-based molecular profiling is constrained by the paucity of Hodgkin Reed-Sternberg (HRS) cells. We summarize emerging strategies, including total metabolic tumor volume (TMTV), serum thymus and activation-regulated chemokine (TARC), and circulating tumor DNA (ctDNA) for more accurate disease burden quantification, noninvasive genotyping, molecular subtyping, and minimal residual disease detection. Together, these tools have the potential to enable a multimodal approach to disease assessment, risk stratification, and response evaluation in cHL.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma subtype, representing a small fraction of Hodgkin lymphoma or an even smaller fraction of B-cell non-Hodgkin lymphoma, depending on the classification schema used. NLPHL is characterized by rare lymphocyte-predominant (LP) cells interspersed within a complex immunologic architecture. NLPHL immunoarchitecture has led to hypothesis-driven research suggesting the pathogenesis of NLPHL may be driven by aberrant immune responses to commensal microorganisms, including Moraxella catarrhalis and Rothia mucilaginosa. NLPHL commonly presents in younger adults with asymptomatic lymphadenopathy in early stages. Although late relapses are a well-known feature of this disease, the prognosis is outstanding, nearly mirroring the average life expectancy in Western populations. Management options must carefully weigh the benefits of treatment against the risks of long-term toxicities, including end-organ damage and secondary malignancies. Options utilizing least-toxic approaches include active surveillance, radiation therapy, and combination chemoimmunotherapy for higher-risk presentations. A recent prognostic score, the LP-IPS, derived from large multicenter datasets, may help personalize approaches for patients at higher risk of morbidity/mortality requiring therapy and identify lower-risk patients for active surveillance or low-toxicity approaches.

This review summarizes contemporary management of Classic Hodgkin Lymphoma in special clinical situations, with a focus on integrating primary clinical trial and observational data to inform individualized treatment decisions. The emphasis is on practical, evidence-based recommendations rather than exhaustive coverage of all regimens.

Older patients age >60 years with advanced-stage cHL have historically had poorer outcomes, attributed to comorbid conditions, performance status, and chemotherapy intolerance. The use of an anthracycline-based chemotherapy backbone has shown strong correlation with improved survival, and the intent of treatment remains curative even in the older population. Strategies to help mitigate treatment toxicity to allow for treatment continuation remain one of the greatest concerns in the treatment of older cHL patients. Avoidance of bleomycin, use of G-CSF in brentuximab vedotin (BV)-AVD, and the use of comprehensive geriatric assessments to assess fitness have allowed for more tailored therapy with improved outcomes in older cHL patients. In clinical practice, identification of comorbid conditions or functional deficits using a comprehensive geriatric assessment allows the provider to intervene earlier, modify risk factors, provider supportive care, and possibly modify therapy based on frailty index. Despite these advances, a standardized frontline treatment regimen has not been universally recognized, but recent advances with the use of targeted therapies such as BV or nivolumab have demonstrated improved outcomes. The recent subset analysis of older patients with advanced-stage cHL treated with N-AVD is the first to suggest an OS benefit in oHL patients, with an acceptable toxicity and tolerability profile. The S1826 study assessed patient-reported QOL measures longitudinally and found that older patients treated with BV-AVD experienced more self-reported neuropathy, diarrhea, and arthralgias/myalgias compared with those on N-AVD. The self-reported tolerability and physician-reported toxicity profile of the S1826 regimen with N-AVD supports the emerging use of N-AVD as frontline therapy in older patients with advanced-stage cHL. Further research is ongoing to tailor treatments for older patients with cHL.

Hodgkin lymphoma is one of the most common cancers in adolescents and young adults (AYAs), a population with distinct biological, clinical, and developmental characteristics. Yet care remains fragmented between pediatric and adult systems contributing to variability in treatment exposure and survivorship outcomes. We synthesized current evidence on AYA HL epidemiology, biology, treatment strategies, supportive care needs, long-term toxicity risk, and survivorship. AYAs have access to multiple efficacious treatment options with high cure rates, but long-term survivors face significant medical, psychosocial, and financial effects with notable risks for cardiopulmonary disease, secondary malignancies, fertility impairment, and unmet psychosocial needs. Harmonized pediatric-adult treatment frameworks, AYA-focused support, and developmentally tailored survivorship care are essential to improving outcomes for AYA HL survivors.