Introduction to Lung Cancer

Kathryn Gold, MD

Clinical Professor

Thoracic/Head and Neck Medical Oncology

Moores Cancer Center

Lung cancer is the most common cause of cancer death in the US

Siegel et al, CA Cancer J Clin, 2011

• Only 17% of all patients diagnosed with lung cancer survive 5 years

Demographics

• Average age at diagnosis of lung cancer is 72
• Some patients are much younger
• More common in men, but women are catching up
• Occurs in all ethnic groups

www.cdc.gov

Risk Factors for Lung Cancer

• Cigarette, pipe, or cigar smoking
• Smokers have a risk of lung cancer ten times higher than non-smokers
• Former smokers have an elevated risk of lung cancer for many years after quitting
• Exposure to second hand smoke, radon, asbestos, air pollution, other agents
• Radiation therapy to the chest or breast
• Many patients have no obvious risk factors
• 15% of patients with lung cancer have never smoked

Histologic Classification of Lung Cancer

Lung Cancer

Small Cell Lung Cancer (SCLC)

Non-Small Cell Lung Cancer (NSCLC)

Squamous Cell Carcinoma

Other

Adenocarcinoma

Adeno-carcinoma

(40%)

Other

(10%)

Squamous

(30%)

SCLC

(20%)

Small Cell Lung Cancer (SCLC)

Clinical Presentation

• Symptoms often develop over a short time
• Cough, dyspnea
• Weight loss
• Paraneoplastic phenomena
• SVC syndrome
• Hoarseness
• Tumors are typically central
• Growth is submucosal
• Hemoptysis is uncommon

Gold KA et al, MD Anderson Manual, 2011

Risk Factors

• Tobacco use
• More than 90% of SCLC occur in smokers
• OR 14.3 for current smokers vs never smokers
• Strongly related to duration and intensity of tobacco use
• OR 47.5 if smoking started prior to age 15
• Additional risk factors:
• Asbestos, benzene, coal tar, radon gas
• Usually as a co-carcinogen with tobacco

Barbone F et al, Chest, 1997

Small Cell Lung Cancer Pathology

• Diagnosed primarily by light microscopy
• Features:
• Small round blue cells
• Sparse cytoplasm
• High mitotic rates
• Immunohistochemistry:
• Neuroendocrine markers (CD56, chromogranin, synaptophysin)
• Positive for keratin
• Usually positive for TTF1

Rekhtman N, Arch Pathol Lab Med, 2010

Staging

• Limited stage
• Tumor confined to a single tolerable radiation port
• Very limited stage: T1 or T2, N0, M0
• Extensive stage
• Anything else
• Malignant pleural or pericardial effusion
• Extrathoracic disease
• Bilateral lung disease
• Increasing push to use TNM staging
• Same system as NSCLC

National Lung Cancer Partnership

Natural History of SCLC

• Without treatment – median overall survival about 6 weeks
• Increased to about 5 months with cyclophosphamide
• Increased to ~12 months with modern chemotherapy

Green RA et al, Amer J Med, 1969

Treatment of Very Limited Disease

• Patients with T1 or T2 tumors and no evidence of nodal or distant disease
• Consider surgical resection with adjuvant chemotherapy
• Five year survival ~31% in small series
• 48% in patients without nodal involvement

Shepherd FA et al, JCO, 1988

Treatment of Limited Stage Disease

• 40% of patients with SCLC
• Poor outcomes with either radiation or surgery alone
• Systemic therapy is necessary
• 1992 meta-analysis
• ~5% survival benefit adding radiation to chemotherapy
• Trials used different chemotherapy regimens and radiation schedules
• Concurrent chemoradiation better than sequential

Pignon JP et al, NEJM, 1992

Prophylactic Cranial Irradiation in LS SCLC

• Brain metastases can be a main site of relapse after chemoradiation
• Meta-analysis shows 5.4% OS benefit at 3 yrs with PCI following CRT for limited stage disease
• Usually 25 Gy in 10 fractions
• Side effects – fatigue, cognitive impairment, memory loss

Auperin A et al, NEJM 1999

Current Standard for LS SCLC

• Concurrent CRT is the standard
• Start chemotherapy ASAP, preferably with cisplatin/etoposide
• Add radiation as soon as you can
• Discuss PCI with all patients

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NCCN Guidelines accessed 11/3/2021

Treatment of Extensive Disease

• Highly chemosensitive
• One of the first solid tumors with survival improvements with chemotherapy
• Chemotherapy should be considered even with borderline PS
• Inpatient if needed

Green RA et al, Amer J Med, 1969

IMpower 133 Phase III Study

• Co-Primary Endpoints: Overall survival and progression free survival

Carboplatin/Etoposide

+ Atezolizumab x 4 cycles

Carboplatin/Etoposide

+ Placebo x 4 cycles

R

Placebo Maintenance

Atezolizumab Maintenance

Untreated Extensive Stage Small Cell Lung Cancer (n=403)

Horn L et al, NEJM, 2018

IMpower 133 Overall Survival Results

Horn L et al, NEJM, 2018

• Standard first line treatment for extensive stage SCLC is platinum/etoposide with immunotherapy (durvalumab/atezolizumab)

Superior Vena Cava Syndrome

Wilson LD et al, NEJM, 2007

Paraneoplastic Phenomena

• More common in SCLC than NSCLC
• Some are mediated by ectopic hormone production
• SIADH, Cushing’s syndrome
• Others mediated by autoantibodies
• Commonly neurological syndromes
• Can be presenting symptom

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SIADH

• Caused by ectopic production of vasopressin (aka anti-diuretic hormone)
• About 10% of patients with SCLC
• Presents with hyponatremia
• Can be severe, accompanied by altered mental status
• Treatment
• Fluid restriction
• Consider saline infusion if symptomatic
• CHEMOTHERAPY

Cushing’s Syndrome

• Caused by ectopic production of adrenocorticotropic hormone (ACTH)
• About 3-5% of patients with SCLC
• Presents with symptoms of hypercortisolism
• Symptoms: weakness, edema, hypertension
• Lab findings: hyperglycemia, hypokalemic metabolic alkalosis
• Associated with poor prognosis

Neurologic Paraneoplastic Syndromes

• Autoimmune in nature
• Onconeuronal antibodies
• Lambert Eaton Syndrome
• Myasthenic syndrome
• Most common neurologic syndrome with SCLC
• Many other types can be seen
• Do not always improve with disease control
• May predict better survival

​

Titulaer MJ et al, Lancet Neurol, 2011

SCLC Conclusions

• SCLC is a highly aggressive, lethal malignancy
• Treatment for limited disease is chemoradiation with cisplatin/etoposide + consideration of PCI
• Treatment for extensive disease is chemotherapy + immunotherapy
• PCI is usually not recommended for extensive stage
• Paraneoplastic phenomena are often tested
• Standard of care changed minimally since the 1990s
• We have not seen the dramatic improvements in SCLC that we’ve seen in other tumor types

Non Small Cell Lung Cancer

Early Stage NSCLC

• Confined to one lung or the lymph nodes within the lung
• “Double digit” nodes
• 5 year survival for node negative lung cancer: 65%
• 5 year survival lung cancer involving N1 nodes: 40%

National Lung Cancer Partnership

Locally Advanced NSCLC

• Spread to the lung nodes in the center of the chest
• “Single digit” nodes
• About 30% of lung cancer patients present with locally advanced disease
• 5 year survival 35-40%

National Lung Cancer Partnership

Metastatic NSCLC (Stage IV)

• Cancer has spread outside the lung
• About 40% of lung cancer patients present with stage IV disease
• Most common sites of metastasis: liver, bone, brain
• Median survival is 14 to 18 months
• 5 year survival:<5% (historically!)

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National Lung Cancer Partnership

Stage Grouping (8^th Edition)

When reading trials, make sure you know what system they used to stage!

NCCN Guidelines version 2.2018

Early Stage NSCLC Treatment

Management of Early Stage NSCLC

• Goal of treatment is CURE
• Surgery is standard of care for medically fit patients
• Lobectomy is superior to segmentectomy for most patients
• Exceptions: nodule less than 2 cm and one of the following:
• Pure adenoca in situ histology
• >50% ground glass appearance on CT
• Long doubling time (>399 days)
• For medically inoperable patients:
• Segmentectomy/wedge resection
• Radiation based approaches

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Adjuvant Chemotherapy: LACE Meta-Analysis

• Meta-analysis with data from 5 large trials with over 4500 patients
• All trials used cisplatin-based doublets
• Overall survival benefit of 5.4% at 5 years with chemotherapy
• Benefit varied by stage
• No benefit in stage IA or IB
• Benefit for stage II and IIIA

Pignon et al, JCO, 2008

Immunotherapy and Targeted Therapy in Early Stage NSCLC

• Increasing role for neoadjuvant chemotherapy in combination with immunotherapy
• Increasing roles for adjuvant targeted therapy and immunotherapies
• Unlikely to be tested on IM boards yet

Locally Advanced NSCLC Treatment

Locally Advanced Lung Cancer

• Usually defined as involving mediastinal lymph nodes
• “old stage III”
• Treated with curative intent but outcomes are poor with traditional therapy
• Concurrent chemoradiation
• 5 year OS < 20% in pre-immunotherapy trials
• Most deaths due to distant metastases

Curran WJ et al, JNCI, 2011

PACIFIC Trial

• Co-primary endpoints: Progression free survival and overall survival

Placebo

Durvalumab 10 mg/kg every 2 weeks for 12 months

R

Stage III NSCLC

Completed chemoRT less than 6 weeks prior to randomization

Antonia SJ et al, NEJM, 2018

PACIFIC Results

Antonia SJ et al, NEJM, 2018

Locally Advanced NSCLC

• For unresectable NSCLC, concurrent chemoradiation followed by consolidation durvalumab is standard of care
• Caveat: may not benefit patients with EGFR/ALK alterations
• Pneumonitis can occur but severe pneumonitis is rare
• Role of concurrent immunotherapy with radiation is unclear
• Should not be used outside of a clinical trial

Metastatic NSCLC Treatment

Advanced Non-Small Cell Lung Cancer

• Metastatic lung cancer is not curable
• Goals of treatment: prolongation of life and improvement of quality of life
• Surgery and/or radiation may play a role for certain patients with stage IV disease
• Prevent fractures in setting of bone mets
• Improve symptoms from brain mets
• Relieve pulmonary obstruction
• Systemic therapy is the mainstay of treatment

NSCLC Treatment in 2004

• Two cytotoxic drugs better than one
• Three cytotoxic drugs not better than two
• Response rates ~20%
• Median OS only 8 months
• 33% alive at 1 year
• We have reached a plateau with standard chemotherapy

Schiller JH et al. N Engl J Med. 2002;346:92-98

Types of Systemic Treatment

Targeted Therapies

Lung Cancer is Not Just One Disease

• A wide variety of molecular alterations are found in lung cancer
• Significant geographic differences in rates of different mutations
• Gene fusions, mutations, and amplification can all be potentially targetable

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Jordan JJ et al, Cancer Discovery 2019

Targeted Therapy vs Cytotoxic Chemotherapy

• Cytotoxic chemotherapy targets rapidly growing cells
• Interference with DNA replication, cell division, etc
• Targeted therapy interferes with cellular growth signals
• Ideally ones that are only active in cancer cells
• E.g., imatinib for CML
• Initial attempts at targeted therapy in lung cancer in unselected groups
• EGFR is frequently overexpressed in NSCLC – so inhibitors of EGFR were studied

BR.21: Erlotinib vs Placebo in Previously Treated NSCLC

• Unselected patients with previously treated NSCLC
• Randomized to erlotinib vs placebo
• 9% response rate with erlotinib
• Modest improvement in progression free survival (PFS) and overall survival (OS)

Shepherd et al, NEJM, 2005

EGFR Mutations in NSCLC

• Exceptional responses seen with erlotinib and gefitinib in some patients
• Led to discovery of EGFR mutations
• Found in about 10-15% of Western lung cancer patients
• More common in Asian patients, non-smokers, women

Lynch et al, NEJM, 2004

EGFR Mutant Lung Cancer Treatment

• Dramatic and prolonged responses seen with EGFR TKIs
• Well tolerated oral drugs
• Diarrhea
• Skin rash

Soria J et al, NEJM, 2018

ALK Rearrangements

Mano, 2008; Soda et al, Nature, 2007

ALK Translocations

• About 5-10% of adenocarcinomas
• Detectable by FISH, IHC, or NGS
• Mostly in young non-smokers
• Responsive to ALK inhibition with oral drugs

Soda et al, Nature, 2007; Kwak et al, NEJM, 2010

ALEX Trial

• Previously untreated patients with ALK positive tumors
• Randomized between ALK inhibitors alectinib vs crizotinib
• Five year survival on alectinib arm: 63%

Peters S et al, NEJM, 2017; Peters S et al, ASCO, 2020

Other Targetable Alterations

• ROS1
• NTRK
• MET exon 14 skipping mutation
• BRAF V600E
• RET fusions
• HER2 mutations
• KRAS mutations

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• Many more under investigation

​

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Targeted Therapy Conclusions

• All patients with adenocarcinoma should have molecular profiling
• Tissue based (preferred, more sensitive)
• Blood based (quicker and easier)
• Consider in patients with squamous cell carcinoma (especially if young, non-smoker)
• More than 40% of lung cancers have alterations targeted by FDA approved drugs
• Many other targets under investigation

Immunotherapy in Metastatic Disease

Why target the immune system to treat cancer?

• The immune system plans a critical role in surveillance
• Immune suppression increases the risk of cancer
• HIV/AIDS
• Solid organ transplant
• Congenital immune deficiency
• Autoimmunity can improve cancer outcomes

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High Dose IL-2 in Melanoma

• High dose IL-2 can result in responses in metastatic melanoma
• Responses often durable (5+ yrs)
• Limitations:
• Low response rates (15-20%)
• Extremely toxic

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Complete Response

All Responders

Partial Response

Atkins MB et al, JCO, 1999

The New York Times, 10/1/18

PD-1/PD-L1 Inhibitors

• PD-1/PD-L1 is an immune brake in interactions between T-cell and tumor cells
• PD-1 inhibitors: nivolumab, pembrolizumab, cemiplimab
• PD-L1 inhibitors: durvalumab, atezolizumab, avelumab

Ribas A, NEJM, 2012

Tumor

Cell

T Cell

Phase I Trial of Nivolumab (BMS-936558)

• Phase I trial in multiple tumor types
• Responses seen in diverse tumor types:
• Melanoma 28%
• NSCLC 18%
• Renal cell carcinoma 27%
• Most responses lasted at least a year

Topalian SL et al, NEJM 2012; Brahmer JR et al, IASLC 2015.

3 year OS Rate 18%

KEYNOTE-189

• Primary endpoints: Progression free survival and overall survival
• Secondary endpoints: response rate, safety, tolerability

Carboplatin/Pemetrexed IV q 3 wks

Carboplatin/Pemetrexed and

Pembrolizumab 200 mg IV q 3 wks

R

Treatment Naïve Metastatic Lung Adenocarcinoma

Gandhi L et al, NEJM, 2018

KEYNOTE-189 Results

• Improved outcomes with pembrolizumab combination:
• Improved OS (12 month OS: 69% vs 49%)
• Improved PFS (median 8.8 vs 4.9 months)
• Improved response (48% vs 19%)
• Increased toxicity
• Patients with all levels of PD-L1 staining benefit

Gandhi L et al, NEJM, 2018

Durability of Response

• In previously treated metastatic NSCLC patients treated with pembrolizumab:
• 15.5% alive at five years
• Many have been off therapy for 3+ years
• Cured?
• Historical: <2% five year overall survival

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Garon EB et al, JCO, 2019

Outcomes for First Line Immunotherapy in PD-L1>50%

Reck M et al, JCO, 2021

Immunotherapy Conclusions

• Immunotherapy with checkpoint inhibitors improves survival in metastatic NSCLC
• Most patients should receive immunotherapy as part of first line therapy
• Exceptions: autoimmune disorders, targetable alterations (ALK, ROS1, EGFR)
• Immunotherapy alone may be sufficient for some patients (PD-L1>50%)
• Responses can be durable

Metastatic NSCLC Treatment Algorithm

IHC for

PD-L1

EGFR/ALK/ ROS1 Positive

Targeted Therapy

No Targetable Alteration

50% Tumor Cells PD-L1 Positive

Pembrolizumab +/- Chemo

<50% PD-L1 Positive

Chemo + Pembro

Molecular Profiling

Therapy following progression: docetaxel is standard but outcomes are poor

Conclusions

Conclusions

• Treatment for lung cancer is rapidly evolving
• Opportunities for better quality of life and longer survival with newer therapies
• It is critical to select the right treatment for the right patient
• Long term survivors of stage IV NSCLC can be seen
• EVERY patient with advanced lung cancer should be offered the opportunity to meet with a medical oncologist
• Clinical trials are the way that treatment improves
• Multiple trials available for all types of lung cancer

Schiller J et al, NEJM, 2002; Soria JC et al, NEJM, 2018; Gandhi L et al, NEJM, 2018; Reck M et al, NEJM, 2016; Peters S et al, NEJM, 2017

Everyone Else

ALK Positive

EGFR Mutant

PD-L1 >50%

Questions?�Thank you!��kagold@health.ucsd.edu�215-681-7021