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The natural history of untreated advanced NSCLC is poor, with a four-to-six-month median survival time. Therapy for patients with advanced NSCLC is, in general, not curative but rather palliative with the intent to prolong survival and preserve the quality of life while minimizing the side effects of treatment.
There are several major international guidelines in NSCLC management, including NCCN and ESMO. They universally refer to three primary treatment options for lung cancer: surgery; radiotherapy; and systemic drug therapy, including chemotherapy [26], [31].
The first question when we decide on NSCLC treatment options is whether the disease is amenable to surgical treatment or, in other words if it is resectable. Patients are staged by Tumor, Node, Metastasis (TNM) classification that mainly evaluates the anatomic burden of disease. The anatomic extent of a tumor is only one aspect that influences the prognosis and treatment decision, and other factors are to be taken into consideration, including:
However, the TNM classification still provides an accurate general strategy. Patients with Stage I or II NSCLC are routinely resected.
In Stage III, only a small proportion of patients in Stage IIIA are resectable. Almost all patients with Stages IIIB or IV disease are unresectable.
There are some exceptions, but they are limited to a small number of patients with T4 disease with limited invasion of the vertebral body, carina, major vessels, or esophagus, but without N2-3 disease or distant metastases, where a successful resection is technically possible. We assume we refer to the unresectable disease when discussing advanced or metastatic NSCLC.
Once surgery for these patients is out of the question, two other options are left: radiotherapy and systemic drug therapy. Radiotherapy is of limited use for patients with advanced and metastatic disease. It could be either palliative to alleviate a symptomatic burden or applied locally to treat brain or bone metastases. Thus, with advanced and metastatic NSCLC, our therapeutic armamentarium has shrunk to one option—systemic drug therapy.
When defining a treatment strategy for advanced or metastatic NSCLC, researchers must consider the TNM stage, the histological diagnosis (adenocarcinoma or squamous), mutation status, age, comorbidities, and performance status (PS). The latter is significant as systemic therapy may be effective in patients with PS of 0-2; supportive care is the only option for patients with PS of 3 and higher. For patients without a driver mutation, initial systemic treatment generally consists of immunotherapy with or without cytotoxic chemotherapy, depending on histology and PD-L1 expression in the tumor. Platinum-based chemotherapy with cisplatin or carboplatin, the backbone of first-line treatment options, may be combined with gemcitabine, vinorelbine, paclitaxel or nab-paclitaxel, or pemetrexed. The choice depends on histology, with cisplatin/pemetrexed being superior to cisplatin/gemcitabine in nonsquamous patients. In contrast, cisplatin/gemcitabine showed better overall survival than cisplatin/pemetrexed in patients with squamous histology [32].
Immunotherapy has become the standard of care in the last ten years, either as a monotherapy or combined with chemotherapy (often considered more effective). Various approaches have been investigated in numerous Phase 3 studies.
Pembrolizumab and chemotherapy (carboplatin/pemetrexed) demonstrated improved response rates (55% versus 29%) and progression-free survival (PFS) and overall survival (OS) rates as compared with the same doublet chemotherapy alone for metastatic nonsquamous NSCLC [33]. Recently published results showed that cemiplimab monotherapy significantly improved OS and PFS compared with chemotherapy in patients with advanced NSCLC with PD-L1 of at least 50% [34]. For patients with PD-L1 expression greater than 50%, the most used drug combination is pembrolizumab with atezolozimab or (less commonly) cemiplimab. If PD-L1 expression is below 50%, the standard of care is chemotherapy plus immunotherapy; again, pembrolizumab is the most common. This regimen showed improved outcomes in OS, PFS, and overall response rate (ORR) compared with chemotherapy alone [35].
The second option is a combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel [36]. With immunotherapy being routine and effective, physicians now face a dilemma that did not exist years ago with conventional chemotherapy—whether and when they can stop the treatment if the disease is not progressing. This question was addressed by a recent study, which showed that patients who completed two years of pembrolizumab and then stopped treatment had excellent long-term outcomes. Notably, 79% of patients who progressed had a partial response or stable disease upon retreatment with pembrolizumab [37].
If an actionable mutation is identified, the first line treatment will utilize one of the tyrosine-kinase inhibitors (TKIs) targeting this particular mutation: osimertinib, erlotinib, afatinib, gefitinib, or dacomitinib for EGFR mutations; lorlatinib, alectinib, brigantinib, ceritinib, or crizotinib for ALK rearrangements; crizotinib or entrectinib for ROS1 positive; dabrafenib and trametinib for BRAF V600E positive; entrectinib or larotrectinib for NTRK positive; and selpercatinib and pralsetinib for RET positive. [26], [31].
Despite significant progress in personalized therapy that led to improvement of overall survival, unmet needs still exist. With the current principle of patient centricity, the primary need is patients’ desire to have lung cancer as a long-term chronic disease with the possibility to maintain a lifestyle similar to their pre-disease state [38]. This global unmet need can be split into several targets for research.
Approximately half of NSCLC patients do not harbor a currently actionable mutation and are therefore not eligible for targeted therapy. For instance, KRAS mutations are seen in 25-30% of NSCLC patients and have long been considered resistant to drug therapy [39]. This mutation is now one of the most promising oncogenic drivers with therapeutic potential in NSCLC. Encouraging preliminary response and safety results for the direct allosteric irreversible inhibition of KRAS G12C has sparked a therapeutic race for FDA approval, with the first drug sotorasib approved in 2021 [40].
Most patients with NSCLC develop primary resistance during immune checkpoint inhibitors monotherapy and only 15-20% achieve partial or complete response. Acquired resistance also occurs in initially responding patients with advanced NSCLC after four to ten months [39]. The mechanisms of resistance to immunotherapy are not yet fully understood.
This includes several mechanisms:
Actionable biomarkers are not single-mutation groups but are heterogeneous, and some variants are associated with the primary resistance to TKIs. For example, EGFR exon 20 insertion mutations represent 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR TKIs.
Many therapeutic agents have limited benefits against metastases in the brain, a common place for both initial presentation (7-10% of NSCLC patients) and progression after treatment (20-40% of NSCLC patients) [41]. Some of the newer drugs may show better CNS penetration, but we need drugs that not only cross the blood-brain barrier but remain there, acting actively against the tumor cells.