Non-Small Cell Carcinoma of the Lung (NSCLC)

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Represents 85-90% of all lung cancers.

Early stage (stage I to III), non-small cell lung cancer accounts for 40 to 45% of all cases of lung cancer.

60 month overall survival rate for NSCLC ranges from 68% in patients with stage 1B disease to 0%-10% in patients with stage IVA-IV B disease.

Lung cancer is the leading cause of cancer related deaths in the US, attributed to approximately 44.7 deaths per hundred persons annually.

Believed to arise from the progression of sequential preneoplastic lesions, including bronchial squamous dysplasia for squamous cell carcinoma and atypical adenomatous hyperplasia for a subset of adenocarcinoma.

The International Association For the Study of Lung Cancer reviewing 12,428 cases of NSCLC found adenocarcinoma with more frequent and squamous cell carcinoma in women(55% versus 25%), while the opposite was true for men (30% versus 57%)(Sculier J-P).

The International Association For the Study of Lung Cancer revealed that squamous cell carcinoma patients have a survival advantage over those with adenocarcinoma or large cell carcinoma, in patients with bronchoalveolar carcinoma had a superior prognosis compared to other subtypes of tumor (Sculier J-P).

Tumor heterogeneity in NSCLC the major reason NSCLC patients with comparable clinical stage and tumor histology can have different clinical outcomes and responses to treatment.

Japanese Joint Committee of Lung Cancer Registry evaluating over 13,000 cases of lung cancer treated with surgery in 2002, was associated with a better prognosis for women and adenocarcinoma with a 5 year survival of 67% for adenocarcinoma versus 53% for squamous cell cancer of the lung: However, adjusting for stage and gender a possible survival advantage for squamous cell carcinoma was present (Asamura H).

Lung cancer incidence and mortality rates are highest in developed countries.

Squamous cell carcinoma of the lung most often centrally located.

Squamous cell carcinoma of the lung associated with smoking and derive from bronchial epithelial cells.

Squamous cell carcinoma of the lung:most express high molecular weight keratin, CK 5 and CK 6 but did not express TTF-1.

p63 is a marker of squamous differentiation.

Almost all types of NSCLC express p53 mutation, which leads to genomic instability and gain of function properties.

Majority of lung cancers, in particular, smoking associated tumors harbor a number of missense mutations, and they are immunogenic due to the presentation of neoantigens.

Smoking is associated with increased mutations, particularly adenonocarcinoma-KRAS mutations.

Nonsmoking related lung cancers are enriched with targetable genetic alterations, with 78 to 90% of these cancers harboring clinically actionable changes with EGFR and ALK fusions.

1.2 million new cases per year worldwide and results in more than 1 million deaths per year.

Less than 5% of patients are younger than 50% years at diagnosis.

15-20% of all newly diagnosed cases are early stage, with tumors <5 cm in diameter.

Approximately 20 to 25% of patients who have a diagnosis of non-small cell lung cancer have susceptible disease, however 30 to 55% of patients who undergo curative surgery have recurrent and ultimately die of their disease.

After NSCLC, recurrence, the five-year overall survival ranges from 2 to 13%.

 

Lobectomy remains the standard of care in medically operable patients for early stage NSCLC. 

Up to 85-90% of patients are not surgical candidates at the time of diagnosis: comorbidities such as COPD, heart disease, continued tobacco use, and patient preference.

Historically conventional fractionated radiation therapy has provided sub optimal local control rates.

Stereotactic body RT (SBRT) has gained preference for these lesions with reported  local control rates of at least 90% at one year and greater than 80% at three years, with largely minimal toxicities.

SBRT has produced equivalent or even superior outcomes compared with surgical resection for operable patients.

Women are more likely to present with earlier stage disease, to have adenocarcinoma and to have a better overall survival than men.

Survival benefit for women persists in untreated patients and when non cancer causes of death are considered.

Epidemiological data suggests women are more susceptible to tobacco carcinogenic effects and are more likely to develop lung cancer as a result of exposure to tobacco.

Studies employing best supportive care result in a 4-6 month median survival, with only 10% of patients alive at 1 year.

Overall median overall survival for patients with advanced disease has improved with the use of chemotherapy by 2 months with 30% surviving at 1 year compared to 10% with best supportive care (Breathnach OS).

Median survival for advanced disease was 2-4 months in 1970 and is presently greater than 12 months.

Median overall survival for patients with advanced stage disease remains dismal, within one year survival rates at 40-50% at best, and two-year survival rates below 15-20%.

Only 3-5% of patients with advanced disease survive 5 years.

Modern chemotherapy doublets has increased median survival time to 8-11 months and with the use of biologic agents median survival times in some cases exceeds 12 months(Breathnach OS, Sandler A).

Only 30-40% of patients with metastases survive one year.

In many lung tumors, a T-cell response is present but is negatively regulated by tumoral expression of checkpoint molecules.

Immune checkpoint inhibitors have limited efficacy in patients with EGFR mutations and can result in increased toxicities in patients who receive immune checkpoint inhibitors followed by a targeted tyrosine kinase inhibitor.

ALK and ROS1 rearranged lung cancers are associated with a younger age at diagnosis.

The frequency of potentially targetable genomic alterations-EGFR ALK, ROS1, BRAF, ERBB2 insertions is significantly higher among patients younger than 50 years.

All these tumors should be tested for driver mutations and rearrangements, which should include EGFR, ALK, ROS1, MET, and BRAF, and PD-L1.

BRAF mutations  are detected in 1.5 to 4.5% of patients with non-small lung cancer.

NSCLC associated with EGFR mutations are associated with better overall survival.

Patients with NSCLC TP53 mutations are associated with shorter survival and contribute to more aggressive biology.

BRAF mutations are found in 1-2% of patients with lung adenocarcinoma, and treatment with BRAF Inhibitors and dabrafenib and vemurafenib have yielded responses.

BRAF Mutations may respond to BRAF inhibitors and a MEK inhibitor trametinib.

EGFR mutations are found in 32.4% of cases worldwide with 10-15% of the caucasian population and nearly 50% of Asian patients with advanced non-small cell lung cancer.

 

ALK rearrangements are seen in 3-7% of cases of non-small cell lung cancer(NSCLC)

 

Approximately 30-40% of patients with ALK translocations have both brain metastasis at diagnosis.

The cumulative risk of CNS metastases can reach 70% at five years after diagnosis in patients with ALK positive disease.

Chromosomal rearrangements of the gene including ROS1 has been found in approximately 1% of patients with NSCLC.

The kinase domains of ALK and ROS1 share homology, therefore some ALK-TKIs have been shown to be effective in patients with ROS1 rearrangement.

Among patients with NSCLC & ROS1 rearrangement crizotinib results in the treatment response rate of 72% and a medium progression free survival of 19 months.

Gene fusions leading to overexpression of ALK protein is found in approximately 5% of patients with metastatic NSCLC.

Crizotinib demonstrated superiority versus the combination of pemetrexed and either cisplatin or carboplatinum as first line treatment with a response rate of 74% versus 45%, respectively and a medium progression free survival of 10.9 months versus seven months, resulting in the adoption of ALK-TKI’s as initial therapy.

Newer ALK-TKIs alecttonib, ceritinib, and brigatinib have a more potent and specific kinase inhibition effect and can be effective in patients with resistance to crizitonib.

The management of patients with NSCLC has been altered by targeted therapy and immunotherapy.

Bone metastases arise in approximately 30-40% of cases.

Brain metastases more common in adenocarcinoma than squamous cell carcinoma.

Patients with NSCLC have a higher prevalence of ALK fusions and EGFR mutations in patients who eventually develop brain metastasis, due to their longer survival.

Brain metastases are more common with the EGFR-mutated or AL K-rearranged tumors.

5 to 10% of patients with NSCLC have concurrent brain metastasis at the time of diagnosis, and 20 to 40% will eventually develop brain metastases.

Stage is the most important prognostic factor.

Nodal status is a more important prognostic variable than tumor size.

Mediastinoscopy is the standard of care for preoperative mediastinal staging in NSCLC.

Mediastinoscopy reported sensitivity and specificity of 87% and 100%, respectively.

Mediastinoscopy reveals that 3-16% of patients with CT scan mediastinal lymph nodes less than 1 cm have tumor involvement.

Mediastinoscopy reveals that 30% of patients with enlarged nodes on CT scan do not have neoplastic changes.

Endobronchial ultrasound guided trans bronchial needle aspirate and trans esophageal endoscopic ultrasound guided fine needle aspiration have advantages over conventional bronchoscopy and blind transbronchial needle aspirate biopsies for sampling mediastinal lymph nodes.

Mediastinal staging in lung cancer with esophageal endoscopic ultrasound guided fine needle aspiration followed by surgical staging, nodal metastases were found in 50% of patients, compared to 35% of patients randomized to surgical staging alone :Thoracotomy was futile in 7% of patients with esophageal ultrasound biopsies compared to 18% of surgically staged patients (Tournoy KG et al).

Early Stage NSCLC (Stage I – III)Patterns of mediastinal nodal metastasis after robotic-assisted pulmonary lobectomy for non-small cell lung cancer:

Retrospective analysis of 159 consecutive cases of early stage I-III NSCLC after robotic-assisted video-thoracoscopic lobectomy with mediastinal LN dissection, mediastinal LN involvement is most commonly found with right side cancers and with upper lobe predominance (Toloza EM et al).

 

Lobectomy remains the standard of care in medically operable patients for early stage NSCLC. 

Up to 85-90% of patients are not surgical candidates at the time of diagnosis: comorbidities such as COPD, heart disease, continued tobacco use, and patient preference.

Historically conventional fractionated radiation therapy has provided sub optimal local control rates.

Stereotactic body RT (SBRT) has gained preference for these lesions with reported  local control rates of at least 90% at one year and greater than 80% at three years, with largely minimal toxicities.

SBRT has produced equivalent or even superior outcomes compared with surgical resection for operable patients.

In the above study the mean age was 67.6 years, most commonly resected histologies were adenocarcinoma (63.5%), squamous cell carcinoma (20.8%), and neuroendocrine carcinoma (8.2%).

Endobronchial ultrasound guided trans bronchial needle aspirate biopsies had better accuracy for nodal staging versus CT scans and pet scans: 94% versus 77%, and 96% versus 73% (Tupayachi MG et al).

Only 25% of all patients with non-small cell lung cancer or alive five years or more after diagnosis.

Approximately 6% of patients with metastatic disease survive to five years.

For patients with newer immunotherapy’s or target therapies five-year survival rates range from 15-50%.

In a Memorial Sloan Kettering study 5 year survival rates of only 48% seen in stage II resected patients with a single positive lymph node and tumor size ≤ 3cm.

Is more advanced in younger patients than older patients.

Most patients, 70, present with advanced unresectable disease, stages IIIB and IV.

25% have resectable disease at the time of diagnosis.

About 40% of patients that are newly diagnosed have stage IV disease.

Forty-five percent of patients present with disease limited enough to permit surgical resection (Deslauriers J).

Lymphatic or vascular invasion associated with highest hazard ratios for local recurrent disease in patients undergoing definitive resection (Shields JW).

50% have disease confined to the thorax.

30% will develop brain metastases.

Approximately 30-40% of 100,000 patient’s who were diagnosed with advanced non-small cell lung cancer each year in the United States will develop brain metastasis during the course of the treatment.

Overall 5-year survival 14%.

Patients with unresectable disease at diagnosis have a five year survival of less than 1% .

Following surgical resection: stage IA patients have a 10% local and a 15% distant recurrence rate, stage IB patients have a 10% local and 30% distant recurrence rate, stage II patients have a 12% local and a 40% distant recurrence rate and stage IIIA patients have 15% local and 60% distant recurrence rate.

Any T2 N2 M0 5-year survival of 23%.

T3 N1 M0 5-year survival 25%.

T3 N0 M0 5-year survival 38%.

T2 N0 M0 5-year survival 57%.

T1 N1 M0 5-year survival 55%.

Surgical treatment can cure as high as 80% of selected T1N0 squamous cell cancer of the lung patients.

Resection for curative intent in Stage IIIA disease associated with a 20-30% 5-year survival.

ANITA trial of patients with Stage IB-IIIA disease, median overall survival for after surgical resection was 43.7 months.

for patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy, postoperative radiation did not improve disease free or overall survival.

ANITA trial use of adjuvant chemo therapy improved otcome, but median overall survival was still only 65.7 months and meta-analyses of NSCLC adjuvant chemo therapy trials suggest a relative survival benefit of just 5% at five years.

Increasing the surgical margin length up to 15 mm during wedge resection of small lung cancer tumors significantly lowers the risk of local recurrence, and no

additional benefit beyond 15 mm, ( Mohiuddin K et al)

Stage IIIA NSCLC is the most controversial among lung cancers for management, as it is not homogeneous, there is a wide range of primary tumor sizes and distribution, there may or may not be mediastinal involvement, and there is a variable lung and other surrounding structures.

If chemoradiation is given preoperatively lower doses of radiation must be used than if chemoradiation is given as definitive therapy.

In stage IIIA disease surgical resection is only rarely the preferred initial treatment.

In general, when stage IIIA lesions are felt to be resectable, neoadjuvant chemotherapy or chemoradiotherapy are equivalent but chemotherapy alone is preferred: higher doses of chemotherapy can be given to control micrometastases, and lowered doses of radiation must be given.

Neoadjuvant chemotherapy for non-small cell lung cancer is associated with an absolute difference in five year recurrence free survival and overall survival compared to surgery alone is only 5 to 6 percentage points:with few patients having a pathological complete response open (0 to 16%).

Neoadjuvant PD-L1 promising for early NSCLC.

National Cancer Database review of 713,043 patients with stage I-IIIA between 1985-1995, before widespread use of adjuvant or neoadjuvant therapy, resulted in 60% survival of completely resected stage I patients and 67% 5 year survival for stage II patients completely resected and a 25% survival for resected stage IIIA patients.

In patients with resectable non-small cell lung cancer, neoadjuvant Nivolumab plus chemotherapy resulted in significant longer event free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone.

Perioperative treatment with nivolumab resulted in significantly longer event, free survival and chemotherapy in patients with resectable NSCLC:CheckMate 77T trial found that neoadjuvant nivolumab plus chemotherapy, followed by surgery and adjuvant nivolumab resulted in significantly longer event free survival than neoadjuvant placebo plus chemotherapy, followed by surgery and adjuvant placebo in patients with resectable stage IIa to IIIB NSCLC.

Such patients at high risk for developing second primary tumors on the order of 2 to 3% per year for at least 10 years after the initial resection.

Intrapulmonary metastasis within the same lobe of the primary tumor is comparable to a T4 lesion and that in a different lobe is comparable with and M1 lesion.

Surgical 5-yer survival for stage I 55%, stage II 25%, stage III 20%, stage IIIB/IV <5%.

After complete resection recurrences leading the death occur mainly in extrathoracic sites.

5-year survival rates for patients with clinical stages IA, IB, IIA, IIB, and IIIA are 61%, 38%, 34%, 24% and 9%, respectively following potentially curative surgery.

5-year survival rates for patients with pathologic stages IA, IB, IIA, IIB, and IIIA are 67%, 57%, 55%, 39%, and 25%, respectively, after surgical resection and staging.

Brain metastases as site of initial treatment failure after resection of NSCLC occur in 6.2-20.3% of cases depending on the stage of disease.

Adjuvant chemotherapy with cisplatin-based regimens improves the survival of patients with completely resected tumors by approximately 5%.

Subgroup analysis of the Lung Adjuvant Cisplatin Evaluation meta-analysis showed no significant benefit in stage IB, a potential detrimental effect in stage IA, indicating surgery for stage I disease is the current standard of treatment.

Survival benefit of cisplatin in advanced NSCLC established in 1995 with a met-analysis of 52 trials with more than 9000 patients showing a 27% reduction in the risk of death at 1 year (NSCLC Collaborative Group).

Adjuvant cisplatin plus vinorelbine prolongs disease free and overall survival in patients with completely resected early stage non-small cell lung cancer.

Phase III trial by Depierre of 373 stage I-IIIA lesions randomized to 2 cycles of neoadjuvant therapy with mitomycin, ifosphamide and cisplatin followed by surgery or surgery alone, 2 cycles of the same chemotherapy were given postoperatively if the patients responded, radiation was given to all T3 or N2 patients: response rate to chemotherapy 64%, with 11% complete responses, median overall survival for chemotherapy group 37 months, vs. 26 months for the surgery only group, disease free survival time of 27 months for the chemotherapy group vs. 13 months for the surgery only group.

In the above study a subset analysis revealed that the benefit of chemotherapy was confined the patients with N1 disease.

First line treatment with chemotherapy regimens have a median survival of 8-10 months, with 1 and 2-year survival rates of 35-45% and 10-20%, respectively.

A maximum of four cycles of first-line chemotherapy is recommended in patients who do not respond to treatment, and a maximum of six cycles are generally given to patients who respond to therapy.

Approximately 50% of patients with advanced NSCLC will have a partial response or stable disease to first line setting chemotherapy typically lasting 3-6 months.

Approximately 25-33% of all lung tumor are neuroendocrine and range from relatively low-grade to highly malignant neoplasms.

Unique and no overlapping gene mutations occur in almost half NSCLC patients, and this is more common in adenocarcinoma.

Blocking genetic alterations in NSCLC tumors can kill tumor cells and result in clinical responses.

EGFR overexpression reported in over 50% of patients.

EGFR mutations are found in approximately 10% of patients with NSCLC in the US, and up to 50% in Asia.

15% of patients diagnosed with an SCLC never smoked cigarettes.

EGFR mutations have been identified in approximately 10% of Western patients, 50% of age Asian patients, it and most frequently in women, in nonsmokers, and in patients with nonmucinous tumors (Paz-Ares L et al).

EGFR mutations define a population of patients with non-small cell lung cancer that have the greatest opportunity to experience a response with treatment with a tyrosine kinase inhibitor of EGFR.

It is likely that pure squamous cell carcinomas do not have activating mutations in EGFR, and if such a mutation is present the cancer is either of mixed histology or poorly differentiated adenocarcinoma.

Non-small cell lung cancer with EGFR mutations represents a molecularly distinct type of lung cancer with first line treatment options that include EGFR targeting tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib.

Afatinib significantly improves outcomes in treatment naïve patients with EGFR mutated NSCLC compared with gefitinib (LUX-Lung7 trial).

Osimertinib effective for T790M mutant NSCLC.

Osimertinib now approved for first line treatment for EGFR mutant NSCLC outperforming erlotinib and geftinib (FLAUNO).

Patients with EGFR mutations treated with osimertinib as initial therapy and improved progression free survival versus those treated initially with first generation EGFR-TKIs gefinitib or erlotinin with progression free survival 18.9 months versus 10.2 months, respectively.

In patients  with stage IB- IIIA EGFR mutation positive NSCLC, the disease free survival was significantly longer among those who received Osimertinib than those who receive placebo (Wu YN).

ADAURA trial-patients  with EGFR harboring mutations  with stage I B to IIIA nonsmall cell lung cancer received chemotherapy with osimertinib demonstrated increased increase disease free survival in the osimertinib group.

First line treatment with osimertinib plus chemotherapy led to significantly longer progression free survival than osimertinib  monotherapy among patients with EGFR mutated advanced NSCLC (FLAURA2 investigators).

Agents that interfere with signal transduction mediated by tyrosine kinases may be associated with improving outcomes in advanced disease.

Patients with squamous cell carcinomas are unlikely to have EGFR mutations and testing in this population is not recommended.

Approximately 85% of NSCLC patients who respond favorably to gefitinib or erlotinib have somatic mutations in the EGFR gene and most of these mutations are on exon 19 deletions or point mutations resulting in a substitution of arginine for leucine at amino acid 858.

The most common EGFR mutations are deletions in exon 19 (exon 19del) and a point  mutation in exon 21(L858R), accounting for 45% and 40% of all patients, respectively.

In these mutations there is an activation of the tyrosine kinase domain, and both are associated with sensitivities to the small molecule EGFR tyrosine kinase inhibitors.

 

Amivantamab Approved for EGFR Exon 20+ NSCLC

Amivantamab is an EGFR mesenchymal epithelial transition factor bispecific antibody with immune with immune cell directing activity with multiple mechanisms of action, and when added to chemotherapy results and superior efficacy, as compared with chemotherapy alone, first line, treatment of patience with advanced NSCLC with EGFR exon 20 insertions.

EGFR  inhibitors frequently associated with a papulopustular rash.

All EGFR  inhibitors are associated with a papulopustular rash,  the most common dermatologic adverse effect of this drug class, and seen in 90% of patients (Perez-Zoler R).

Multikinase  inhibitors  sorafenib and sunitinib are associated with a papulopustular rash that is less frequent and milder than  the rash associated with EGFR inhibitors.

Approximately 30% of patients with advanced disease are high expressors of PD-1.

Microvessel count, an indication of angiogenic effect, is a predictor of poor prognosis in patients with NSCLC.

Mutations in the exons 18-21 around the ATP binding pocket of the tyrosine kinase domain leads to enhanced tyrosine kinase activity in response to epithelial growth factor and increased sensitivity to inhibition by gefitinib and erlotinib.

Such mutations are more common in women, in adenocarcinomas, in nonsmokers and in Japanese compared to Westerners.

Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in the sub group of non-small cell lung cancers and represent 2-7% of such tumors.

Patients with ALK rearrangements tend to be younger than patients without such rearrangements.90% of ALK positive lung cancer patients have never smoked or are light smokers.

ALK positive lung cancer patients do not overlap with the EGFR mutation, and patients typically have either ALK rearrangement or EGFR mutation, but not both.

Most patients with ALK rearrangements have had little or no exposure to tobacco and have adenocarcinomas.

90% of ALK positive lung cancer patients have never smoked or are light smokers.

ALK positive lung cancer patients do not overlap with the EGFR mutation, and patients typically have either ALK rearrangement or EGFR mutation, but not both.

In a small proportion of lung cancer patients ALK rearrangements are present and is a result of a small inversion within chromosome 2p, leading to a fusion of a portion of the EML4 gene with exons 20 through 29 of ALK.

Crizotinib, and oral active ALK inhibitor has received 57% overall response rate, 87% disease control rate and 6 month progression free survival of 72% in heavily pretreated patients with adenocarcinoma (Bang Y et al).

Ceritinib in ALK rearranged NSCLC is highly active in advanced disease, including those progressing on Crizotinib treatment (Shaw AT et al).

1-20% of non-small cell carcinomas of the lung, especially adenocarcinomas are neuroendocrine positive by immunohistological or ultrastructural evidence.

Adenocarcinomas account for approximately 30% of non-Small Cell Carcinoma of the Lung (NSCLC).

Malignant epithelial tumors with glandular differentiation.

Subdivide into acinar, papillary, bronchioloalveolar, solid adenocarcinoma with mucin production, and mixed pattern-type.

Tumors are derived from alveolar, bronchial, or bronchiolar epithelial cells.

Atypical adenomatous hyperplasia can be a potential precursor of nonmucinous bronchioloalveolar carcinoma.

Adenocarcinomas metastasize primarily via lymphatic and hematogenous routes.

Approximately 20% of patients with adenocarcinoma have distant metastasis at the time of diagnosis.

Most common sites of metastases for adenocarcinoma of the lung include brain, bone, adrenal glands, and liver.

Most adenocarcinoma of the lung lesions are thyroid transcription factor one (TTF1) positive.

Adenocarcinomas rather than squamous cell carcinoma is associated with ALK rearrangements.

Mucinous bronchoalveolar carcinoma tumors from bronchial mucinous cells are generally TTF-1 negative and CK 20 positive.

The National Lung Screening Trial (NLST) screened more than 53,000 current or former smokers aged 55-74 years with spiral CT scans of the chest: 20% fewer lung cancer deaths among screened participants then those screened with chest x-rays, and all cause mortality with 7% lower in the group screened by the helical CT.

Adenocarcinomas with >5% of neuroendocrine cells are clinically aggressive tumors.

10-20% of cases show neuroendocrine differentiation.

Neuroendocrine differentiation found in all histologic types of lung cancer but is more frequent in adenocarcinoma and large cell carcinoma.

Stage I carcinomas of the lung with neuroendocrine differentiation and synaptophysin positive have a poor prognosis and higher frequency of recurrence and lower survival rates.

Approximately two-thirds of patients with NSCLC are 65 years of age or older and 40% are older than 70 years.

Combination chemotherapy produces a 2-fold increase in response rate over single agent treatment, but is associated with a 3.6-fold increase in the likelihood of suffering a treatment related death.

Most stage I and II patients recur with two-thirds recur systemically and one-third locally.

Surgical resection is the standard of care for early stage NSCLC with most patients undergoing lobectomy with pneumonectomy reserved for a minority of patients to complete resection.

In a randomized prospective trial conducted by the Lung Cancer Study Group compared limited resection lobectomy for patients with stage IA (T1N0) non-small cell lung cancer: It was a 75% increase in recurrence rates associated with limited resection, and a 50% increase in cancer specific death compared to patients who underwent lobectomy (Ginsberg R, Rubenstein L).

Segmentectomy is probably equivalent in terms of 5 year survival rates compared to lobectomy for a clinically stage IA tumor that is less than 2 cm (Okada M et al).

Bisphosphonates decrease risk of skeletal events.

Doublet chemotherapy with cisplatin or carboplatin along with vinorelbine, gemcitabine, paclitaxel or docetaxel standard treatment.

Bimodality Lung Oncology Team (BLOT) trial in clinical stage IB, II and IIA disease received preoperative either 2 or 3 cycles of paclitaxel and carboplatin and 2 or 3 cycles after surgery: at 56 months the group receiving 2 preoperative and 3 postoperative cycles had a 56% partial response rate and for the 3 preoperative and 2 postoperative cycles a 38% response rate, with a 63% vs 38% 3 year survival rates.

Intergroup Trial 0139 of 429 patients with potentially resectable stage IIIA NSCLC were randomized to concurrent radiation with a platinum and Etoposide agent for two cycles followed by surgical resection followed by two cycles of platinum and Etoposide, or to concurrent radiation with four cycles of platinum and Etoposide: the initial five year progression-free survival appeared to be in favor of the surgical resection arm. 22% vs. 11%, however the overall survival data was not significantly difference between the two arms at 27% vs. 20%.

Intergroup Trial 0139 revealed a 26%, postoperative mortality associated with the pneumonectomy and a benefit was seen among those patients who underwent a lobectomy.

EORTC study randomized 579 patients with stage IIIA NSCLC who had received three cycles of chemotherapy with cisplatin, to radiation or surgery: the five year overall survival in the radiation arm 14% in the surgical arm was 16%: in this trial, it did not appear that surgical resection after chemotherapy and radiation added any additional benefit.

JBR.10 trial compared adjuvant cisplatin/vinorelbine for four cycles with observation alone in 482 completely resected resected IB (T2N0) or IIB (T1-2N1)disease:Median overall survival 93 months in adjuvant group vs. 73 months in observation group, a 31% reduction in risk of death (Butts CA).

Non-small cell lung cancer adjuvant chemotherapy after resection of stage II-IIIA disease improves survival and is recommended therapy.

Non-small cell lung cancer Stage I adjuvant therapy limited to patients with a resected tumor 4 cm or larger.

Adjuvant Lung Cancer Trial reported a 4% absolute 5 – year survival increase in an overall survival hazatd ratio of 0.86 in favor of a platinum-based chemotherapy given for four Cycles compared with observation.

JBR.10 trial median overall survival was increases in stage II patients but not in stage IB patients, and at 5 years there was a 7% survival advantage in stage IB patients ans 20% in stage II patients (Butts CA).

Addition of bevacizumab to chemotherapy extends survival in advanced nonsquamous cell NSCLC.

The addition of bevacizumab to adjuvant chemotherapy does not improve overall survival for patients with surgically resected early non-small cell lung cancer and does not have a role in this setting (Wakelee HA).

ECOG 4599 trial with bevacizumab added to carboplatin/paclitaxel prolonged survival from 10.2 months to 12.5 months among 878 patients previously untreated with advanced disease.

Second line treatment with docetaxel or pemetrexed have shown improved survival over supportive care alone.

In a phase 3 prospective randomized trial of docetaxel versus best supportive care in NSCLC patients previously treated with platinum-based chemotherapy, docetaxel treatment resulted in significant probation of survival of 7.5 months versus 4.6 months (Shepherd FA et al).

Response rate in refractory patients 8.9% with a survival of 6.7 months with erlotinib.

Patients with elevated CEA more likely to be sensitive to gefitinib than patients with a normal CEA.

Phase II studies as first time treatment for advanced NSCLC produced overall response rates of 15.8-23.3%, with median survival of 7.2-9.2 months with 1 year survival rates of 25-32%.

Non-small cell cancer of the lung (NSCLC)-Phase I combination treatments with pemetrexed and cisplatin in first line treatment of advanced NSCLC have response rates 38.9-44.8% with a median survival of 8.9-10.9 months and a median survival at 1 year 50%.

Response rate to second line treatment is less than 10% with pemetrexed or docetaxel.

Phase three open label randomized study of Pemetrexed plus cisplatin vs. gemcitabine plus cisplatin in 1725 patients: median survival 10.3 months for both treatment arms, median progression free survival 4.8 months for Pemetrexed plus cisplatin and 5.1 months for gemcitabine plus cisplatin, response rates 27.1% for Pemetrexed plus cisplatin and 24.7% for gemcitabine plus cisplatin, median survival was 9.4 months for Pemetrexed plus cisplatin in squamous cell lung cancer and 10.8 months for gemcitabine plus cisplatin suggesting that Pemetrexed was more beneficial for nonsquamous cell lung cancers and gemcitabine plus cisplatin better for squamous cell histology (Scagliotti et al).

In a phase III study a maintenance pemetrexed plus best supportive care versus placebo immediately following induction therapy with pemetrexed plus cisplatin for advanced non-small cell lung cancer (PARAMOUNT) study: Pemetrexed maintenance subapical he improved clinical benefit with a 36% reduction in the risk of progression.

Comparing paclitaxel and carboplatin to the same agents plus bevacizumab revealed significant increases in response rate of 10% vs, 27%, progression free survival of 4.5 months vs 6.4 months and survival of 10.2 months vs 12.5 months in patients with mainly stage IIIB/IV nonsquamous NSCLC.

The addition of bevacizumab to standard chemotherapy is now first-line choice of treatment for nonsquamous cell NSCLC, in the absence of hemoptysis, CNS metastases and no ongoing therapeutic anticoagulation.

For patients with recurrent or refractory NSCLC treated with pemetrexed or docetaxel chemotherapy, bevacizumab plus chemotherapy or bevacizumab and erlotinib resulted in progression free survival of 3, 4.8 and 4.4 months, respectively with response rates of 12.2, 12.5 and 17.9%, respectively.

AVAIL (Avastin in Lung )trial, a European trial of 1,043 patients with previously untreated advanced or recurrent NSCLC randomized to cisplatin and gemcitabine alone or the same agents with bevacizumab: results in a progression free survival 5-10% better with the bevacizumab chemotherapy combination and no differences were noted for bevacizumab at 7.5 mg/kg or 15 mg/kg doses.

ECOG 1594 study comparing paclitaxel/cisplatin, gemcitabine/cisplatin, docetaxel/cisplatin and paclitaxel/carboplatin: no significant differences in study arms and overall response rte was 19%, median survival 7.9 months, 1 yer survival 31-36%, and 2 yer survival 10-13% (Schiller JH).

Women in the group receiving paclitaxel, carboplatin and bevacizumab had more hypertension, constipation and abdominal pain than men.

Hemoptysis and pulmonary hemorrhage occurred in only 2.3% of patients treated with bevacizumab and chemotherapy with nonsquamous histology.

In a phase II study of bevacizumab and chemotherapy fatal hemorrhage was related to central cavitating lung lesions, and this is more frequent in squamous cell cancers (Johnson DH).

In study of 106 the valuable patients with advanced non-small cell lung cancer who have previously treated brain metastasis also treated with bevacizumab and chemotherapy there was a minimal risk of intracerebral hemorrhage (PASSPORT Trial, Socinski, MA).

In a study of randomly assigned 272 patients to receive Nivolumab at a dose of 3 mg/kg every 2 weeks or docetaxel every 3 weeks: Among previously treated squamous cell NSCLC overall survival, response rates, progression free survival were significantly better with Nivolumab, regardless of PD-L1 expression.

Nivolumab plus ipilimubab resulted in a longer duration of overall survival than chemotherapy in patients with NSCLC, independent of PC-L1 expression.

Patients with advanced NSCLC treated with nivolumab achieve the greatest duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage: four year overall survival was 14%.

Women are more likely to have mutations of the epidermal growth factor receptor that confer a greater clinical benefits from EGFR inhibitors.

Nab-paclitaxel protein-bound particles is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

PET scan findings of a low normalized SUV max within the primary tumor is significantly associated with having an EGFR mutation, and high FDG avidity with a normalized SUV 5 or greater may be predictive of the wild type EFGR genotype.

Higher levels of estrogen may influence the development of progression of this type lesion.

Erlotinib (Tarceva) the epidermal growth factor receptor-tyrosine kinase inhibitor has been shown to have superior survival compared to placebo in salvage setting.

Erlotinib (Tarceva)indicated for the first line treatment of patients with metastatic non-small cell lung cancer whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 substitute mutations.

SATURN (Sequential Tarceva in Unresectable Non-Small Lung Cancer) a maintenance trial in patients with advanced, inoperable, metastatic NSCLC treated with first-line platinum based doublet-responders treated with erlotinib or placebo: greatest benefit in patients with EGFR mutation positive group with a 90% reduction in the risk of disease progression compared to placebo, but only 11% had such a mutation.

In a randomized controlled study of 230 patients with metastatic, non-small cell lung cancer and EGFR mutations and who had not previously received chemotherapy, received gefitinib or carboplatin-paclitaxel: progression free survival was significantly longer in the gefitinib group with a median progression free survival of 10.8 months versus 5.4 months in the chemotherapy group, a higher response rate of 73% versus 23.6 months in the chemotherapy group (Makoto M et al).

63 patients with stage III/IV cancer having failed one or more chemotherapy regimens and tried on sunitinib 50 mg/day for 4 weeks followed by 2 weeks of rest resulted in a 9.5% response rate with a 42.9% stable disease rate.

Patients with activating mutations in the epidermal growth factor receptor

(EGFR)domain or EML4-ALK translocation benefit from first-line treatment with erlotinib or crizotinib, respectively.

ALK lung tumors can be inhibited by anaplastic lymphoma kinase inhibitor crizotinib, an oral small molecule inhibitor, with a response rate of 57% (Kwak EL et al).

Crizotinib (Xalkori) in patients with advanced ALK positive NSCLC has a 1 year survival rate of 74% and a 2 year overall survival rates of 54%, compared to 44% and 12%, respectively, in matched patients who did not receive crizotinib (Shaw AT et al).

Dabrafenib (Tafinlar) approved for the treatment of patients with metastatic BRAF V600E mutation-positive non-small cell lung cancer (NSCLC) who have received at least one prior line of platinum-containing chemotherapy.

Activating BRAF V600E mutations are present in approximately 1.6% of patients with NSCLC, primarily in the adenocarcinoma.

A phase II study showed durable antitumor activity, including an overall partial response rate of 40% in patients with BRAF V600E mutation–positive pretreated NSCLC patients.

Using a BRAF inhibitor dabrafenib and a MEK inhibitor in patients with metastatic BRAF mutant NSCLC the response rate was 64% with the median progression free survival of 11 months.

Heavy smokers do not benefit from dabrafenib.

SRT (Stereotactic radiation therapy) protocols administered biologically effective doses of equal or greater than 100 Gy, which confers superior tumor kill compared to the 70-80 Gy administered with conventional radiation.

RTOG 0617 study of 500 patients with stage IIIA/IIIB non-small cell lung cancer compared 60 Gy to standard 74 Gy radiation: The lower dose was associated with a median overall survival rate at one year of 81% compared to 70.4% for the high dose regimen.

SRT In patients with stage I non-small cell lung cancer 3 and five year local control rates with approximately 100 Gy are 95% and 84%, respectively.

SRT to the long is associated with rib fractures and pneumonitis affecting up to 5% of patients.

KRAS is the most common mutation in NSCLC.

KRAS found in 15-40% of NSCLC cases are considered a marker of aggressive tumor biology.

KRAS  mutated non-small cell lung cancers are generally associated with smoking, current or former, increased program death ligand-1 expression on tumors, increased tumor mutational burden, and increased tumor infiltrating lymphocyte count.

For a dose of at least 45 Gy in three fractions of stereotactic radiation, the average rate of adorable local control of non-small cell lung cancer exceeds 90%, and the average reported three-year overall survival exceeds 50%.

Postoperative radiation therapy recommended for patients with high risk for local relapse, such as those with positive surgical margin, or extensive nodal disease and associated with decreased local recurrence rate.

Postoperative radiation therapy has not shown survival benefit and in stage I and II disease may be associated with a survival detriment.

Recent studies reveal that postoperative radiation therapy is safe and not associated with excessive deaths from intercurrent disease.

Use of combined chemoradiation in patients with unresectable NSCLC associated with median survival times of 13-14 months and 5 year survival rates as high as 15-20%.

Concurrent radiation therapy and chemotherapy in patients with locally advanced, inoperable NSCLC, with good performance status and minimal weight loss, the expected four year overall survival and median survival is 21% and 17 months, respectively (Curran WJ et al).

Radiation dose has remained at 60 Gy for more than 30 years as the standard dose for NSCLC-this dose is unfortunately associated with a local failure of up to 85%.

In early NSCLC SEER data indicates coventional fractionated radiation is associated with improved overall survival, with a 3 year actuarial survival of approximately 30%.

Conventional radiation with treatment on the order of 60Gy given in 30 fractions has a likely crude local failure rate of 50% or greater (Sibley GS et al).

Hyperfractionated or accelerated radiotherapy in patients with nonmetastatic NSCLC associated with a 2.5% absolute survival benefit at 5 years compared to conventional treatment schedule of radiation: no improvement in progression free survival. (Maugen A et al).

With modern treatments radiation in the range of 70-74 Gy can be achieved safely with concomitant chemotherapy.

Postoperative radiotherapy significantly improves overall survival and decreased lung cancer mortality in patients with IIIA, iN2 disease with six or more positive lymph nodes, but is not recommended for patients with N0 and N1 disease.

Response rates for patients with metastatic NSCLC treated with the platinum and taxane previously is only 2% for a third line treatment and 0% for fourth line chemotherapy approach.

In general patients with performance status greater than 3 do not benefit from chemotherapy, except for erlotinib for epidermal growth factor receptor mutation positive patients and Crizotinib for ALK positive patients.

Pembrolizumab in NSCLC with >50% PD-1 expression associated with progression free survival of 10.3 months compared with chemotherapy of 6 months in treatment naïve advanced metastatic patients.

Pembrolizumab approved as first line therapy in combination with carboplatin and pemetrexed in nonsquamous metastatic NCCLC, regardless of PD-L1 expression.

 

In the KEYNOTE-010 trial, 35% of patients with relapsed nonsmall cell lung cancer (NSCLC) treated with pembrolizumab were still alive at 3 years, according to long-term results from a pivotal clinical trial.

 

Among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

 

KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

 

In the phase three KEYNOTE-407 study on squamous NSCLC, chemotherapy with pembrolizumab had a significantly longer overall survival and progression severe free survival than with chemo therapy alone.

Patients with PD-L1 positive NSCLC demonstrated a 45.5% objective response rateto pembrolizumab compared to 29.8% with chemotherapy in the phase III KEYNOTE-24 trial.

pembrolizumab in the KEYNOTE-67 study found that among patients with resectable, early stage, non-small cell, lung, cancer, neoadjuvant Pembrolizumab, plus chemotherapy, followed by resection and adjuvant, pembrolizumab, significantly improved event, free survival, major, pathological, response, and pathological complete response as compared with neoadju in chemotherapy alone, followed by surgery: overall survival did not different significantly between the groups in this analysis. (Wakely,H).

Carboplatin/Pemetrxed is the most commonly used first line chemotherapy regimen in the United States for advanced non-squamous NSCLC.

KEYNOTE 189 phase III trial, the combination of Pembrolizumab with standard chemotherapy in the front line setting reduced the risk of death by more than 50% of patients with non-squamous NSCLC without EGFR or ALK mutations.

IMpower110 study adjuvant atezolizumab improved overall survival versus platinum-based chemotherapy for non-small cell lung cancers whose resected tumors expressed high levels of PD-L1.

In the above trial demonstrated a significant benefit in overall survival for chemotherapy plus Pembrolizumab with an estimated 12 month overall survival rate of 69.2% versus 49.4% for chemotherapy alone.

In KEYNOTE 189 trial PD-1 overall survival was improved irrespective PD-L1 status.

 

In the KEYNOTE-024 phase III trial compared Pembrolozuzmab to platinum based chemotherapy as first line treatment for metastatic NSCLC with PD-L1 expression levels 50% or greater:  Response rate for Pembrolizumab monotherapy was 44.8% versus 27.8% for chemotherapy alone.

In the above study the median overall survival was longer with Pembrolizumab  at 30 months compared with chemotherapy at 14.2 months.

Avelumab has antitumor activity in patients with progressive or treatment resistant NSCLC.

Durvalumab in the PACIFIC study demonstrated in patients with stage III NSCLC there was a significant benefit in survival with adjuvant durvalumab after chemotherapy compared with placebo.

In the PACIFIC  trial Standard chemotherapy/radio therapy followed by Durvalumab have maintenance for one year is now the standard of care in unresectable stage III non-small cell lung cancer.

In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival, than chemotherapy alone (Provencio, M).

The addition of toripalimab to perioperative chemotherapy, has shown improvement and event free survival for patients with resectable stage III NSCLC.

KEYNOTE-671 trial: patients with stage II, IIIA, IIIB received four cycles of neoadjuvant, pembrolizumab or placebo in addition to chemotherapy, followed by surgical resection: event, free survival, and possible overall survival benefit are emerging, increased pathological complete response, and major pathological response as well.

Immunotherapy in NSCLC takes time to be effective and is generally less effective in patients with cancer is that is progressing quickly.

In a Japanese study, chemotherapy plus immune checkpoint inhibitor combination did not improve survival and increased the incidence of grade 3 and higher immune related adverse events compared with immune checkpoint inhibitor alone in patients 75 years and older:it may be recommended immune checkpoint inhibitors alone be used for older patients with PDL-1 positive NSCLC.

Cemiplimab-rwlc monotherapy for use in the frontline treatment of patients with advanced non–small cell lung cancer (NSCLC) with a PD-L1 expression level of 50% or higher.

Tumors with low tumor mutation burden, such as EGFR, ALK/ROS-mutated NSCLC appear to have low objective response rates for immunotherapy around 4%, arguing for reserving immunotherapy until after exhausting more effective targeted and chemo therapy options for this subset of patients.

Drug therapies for non- small cell lung cancers:

Angiogenesis inhibitor

bevacizumab Avastin

(Genentech) 100mg, 400mg soln for IV infusion after dilution 15mg/kg once every 3 weeks IV.

Antimetabolites

gemcitabine Gemzar 200mg, 1g pwd for IV infusion after reconstitution 1000mg/m2 on Days 1, 8, and 15 of each 28 day cycle; or 1250mg/m2 on Days 1 and 8 of each 21 day cycle

methotrexate 25mg/mL soln for IV, IM, intra-arterial, or intrathecal administration after dilution

pemetrexed Alimta

(Lilly) 500mg. 500mg/m2 on Day 1 of each 21-day cycle

Antimicrotubule agents

docetaxel Taxotere

(Sanofi Aventis) 40mg 75mg/m2 once every 3 weeks

paclitaxel Taxol

(Bristol Myers Squibb) 135mg/m2 every 3 weeks

paclitaxel [bound to albumin (human)] Abraxane

(Abraxis Oncology) 100mg/vial 100mg/m2 on Days 1, 8, and 15 of each 21-day cycle

vinorelbine Navelbine

10mg/mL soln for IV inj after dilution Monotherapy: 30mg/m2 once weekly Combination therapy: 25mg/m2 once weekly given every 4 weeks; or 30mg/m2 once weekly given on Days 1 and 29, then every 6 weeks

Tyrosine Kinase Inhibitors

crizotinib Xalkori

(Pfizer) 200mg, 250mg caps 250mg twice daily

erlotinib Tarceva

(Genentech) 25mg, 100mg, 150mg tabs 150mg once daily

PD-1 checkpoint inhibitors

Durvalumab

Ramucimab

Nivolumab

Pembrolizumab

Atezolizumab

Lazertinib