EGFR Testing For Advanced Lung Cancer

Testing for epidermal growth factor receptor mutations is an important step in the evalu­ation process for systemic ther­apy in patients with metastatic or recurrent non–small cell lung cancer according to up­dated recommendations issued by the American Society of Clinical Oncology and the Na­tional Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) that pa­tients with advanced non–small cell lung cancer (NSCLC) who are being considered for treat­ment with one of the tyrosine kinase inhibitors (TKIs) that tar­get the epidermal growth factor receptor (EGFR) should under­go EGFR-mutation testing. 

Oncologists have learned that NSCLC is “really a collection of genetically distinct diseases,” ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to “treat pa­tients with drugs that target the molecular drivers of their spe­cific tumors rather than using a one-size-fits-all approach.”

The NCCN earlier updated its clinical management guide­lines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s an­nual conference. 

Both groups based their endorse­ments on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy not­ed the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients de­lays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefi­tinib (Iressa) among EGFR mutation–positive patients. 

The last question is of particular in­terest, because gefitinib is not Food and Drug Association approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progres­sion-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefi­tinib or standard carboplatin and paclitaxel chemotherapy. 

IPASS demonstrated that EGFR mu­tation strongly predicted a lower risk of progression on gefitinib vs. chemother­apy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57). 

Similarly, in a pooled analysis of clin­ical outcomes of NSCLC patients who were treated with erlotinib, EGFR mu­tations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a dif­ference in overall survival among treated patients with and without EGFR muta­tions, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mu­tation in patients with NSCLC “confers a high level of resistance” to TKIs. 

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an associ­ation between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommen­dation for sequencing, as well as a rec­ommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lym­phoma kinase (ALK) fusion gene, Dr. Et­tinger said. 

“Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy,” he said, noting that the inves­tigational ALK-tar­geting drug crizotinib, in par­ticular, has demon­strated positive results in early studies of NSCLC patients with echinoderm mi­crotubule-associat­ed proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic ther­apy, patients with adenocarcinoma, large cell carcinoma, or NSCLC “not other­wise specified” who have an Eastern Co­operative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line thera­py should be treated with erlotinib, ac­cording to the NCCN guidelines. 

Alternatively, the guidelines state that gefitinib can be used in place of erlotinib “in areas of the world where it is avail­able.” 

For patients in whom the EGFR mu­tation is discovered during chemothera­py, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment.

For patients whose EGFR status is negative or unknown, even in the pres­ence of clinical characteristics that might be suggestive of a mutation (for exam­ple, female, nonsmoker, Asian race), con­ventional chemotherapy is recommended, Dr. Ettinger said. 

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the grow­ing clinical importance of molecularly defined subgroups of adenocarcinoma signals a “new era of personalized med­icine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy.” 

The implemen­tation of routine, simultaneous testing of multiple markers will likely be con­ducted on all patients prior to treat­ment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, includ­ing obtaining adequate tumor materi­al at the time of diagnostic biopsy and developing testing platforms “that si­multaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges.”

The updated NCCN Guidelines for NSCLC are posted at www.nccn.org. The ASCO PCO is posted at www.asco.org/ascov2/Practice+&+Guidelines/Guidelines/Provisional+Clinical+Opinion.

Dr. Ettinger has consultancy agree­ments with the a number of pharma­ceutical companies Dr. Keedy receives commercial research support from Ari­ad Pharmaceuticals, Ziopharm Oncolo­gy, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with a number of pharmaceutical companies. Dr. Doebele disclosed re­search funding from Lilly, ImClone Sys­tems, and Pfizer.

Testing for epidermal growth factor receptor mutations is an important step in the evalu­ation process for systemic ther­apy in patients with metastatic or recurrent non–small cell lung cancer according to up­dated recommendations issued by the American Society of Clinical Oncology and the Na­tional Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) that pa­tients with advanced non–small cell lung cancer (NSCLC) who are being considered for treat­ment with one of the tyrosine kinase inhibitors (TKIs) that tar­get the epidermal growth factor receptor (EGFR) should under­go EGFR-mutation testing. 

Oncologists have learned that NSCLC is “really a collection of genetically distinct diseases,” ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to “treat pa­tients with drugs that target the molecular drivers of their spe­cific tumors rather than using a one-size-fits-all approach.”

The NCCN earlier updated its clinical management guide­lines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s an­nual conference. 

Both groups based their endorse­ments on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy not­ed the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients de­lays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefi­tinib (Iressa) among EGFR mutation–positive patients. 

The last question is of particular in­terest, because gefitinib is not Food and Drug Association approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progres­sion-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefi­tinib or standard carboplatin and paclitaxel chemotherapy. 

IPASS demonstrated that EGFR mu­tation strongly predicted a lower risk of progression on gefitinib vs. chemother­apy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57). 

Similarly, in a pooled analysis of clin­ical outcomes of NSCLC patients who were treated with erlotinib, EGFR mu­tations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a dif­ference in overall survival among treated patients with and without EGFR muta­tions, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mu­tation in patients with NSCLC “confers a high level of resistance” to TKIs. 

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an associ­ation between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommen­dation for sequencing, as well as a rec­ommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lym­phoma kinase (ALK) fusion gene, Dr. Et­tinger said. 

“Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy,” he said, noting that the inves­tigational ALK-tar­geting drug crizotinib, in par­ticular, has demon­strated positive results in early studies of NSCLC patients with echinoderm mi­crotubule-associat­ed proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic ther­apy, patients with adenocarcinoma, large cell carcinoma, or NSCLC “not other­wise specified” who have an Eastern Co­operative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line thera­py should be treated with erlotinib, ac­cording to the NCCN guidelines. 

Alternatively, the guidelines state that gefitinib can be used in place of erlotinib “in areas of the world where it is avail­able.” 

For patients in whom the EGFR mu­tation is discovered during chemothera­py, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment.

For patients whose EGFR status is negative or unknown, even in the pres­ence of clinical characteristics that might be suggestive of a mutation (for exam­ple, female, nonsmoker, Asian race), con­ventional chemotherapy is recommended, Dr. Ettinger said. 

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the grow­ing clinical importance of molecularly defined subgroups of adenocarcinoma signals a “new era of personalized med­icine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy.” 

The implemen­tation of routine, simultaneous testing of multiple markers will likely be con­ducted on all patients prior to treat­ment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, includ­ing obtaining adequate tumor materi­al at the time of diagnostic biopsy and developing testing platforms “that si­multaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges.”

The updated NCCN Guidelines for NSCLC are posted at www.nccn.org. The ASCO PCO is posted at www.asco.org/ascov2/Practice+&+Guidelines/Guidelines/Provisional+Clinical+Opinion.

Dr. Ettinger has consultancy agree­ments with the a number of pharma­ceutical companies Dr. Keedy receives commercial research support from Ari­ad Pharmaceuticals, Ziopharm Oncolo­gy, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with a number of pharmaceutical companies. Dr. Doebele disclosed re­search funding from Lilly, ImClone Sys­tems, and Pfizer.

Testing for epidermal growth factor receptor mutations is an important step in the evalu­ation process for systemic ther­apy in patients with metastatic or recurrent non–small cell lung cancer according to up­dated recommendations issued by the American Society of Clinical Oncology and the Na­tional Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) that pa­tients with advanced non–small cell lung cancer (NSCLC) who are being considered for treat­ment with one of the tyrosine kinase inhibitors (TKIs) that tar­get the epidermal growth factor receptor (EGFR) should under­go EGFR-mutation testing. 

Oncologists have learned that NSCLC is “really a collection of genetically distinct diseases,” ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to “treat pa­tients with drugs that target the molecular drivers of their spe­cific tumors rather than using a one-size-fits-all approach.”

The NCCN earlier updated its clinical management guide­lines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s an­nual conference. 

Both groups based their endorse­ments on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy not­ed the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients de­lays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefi­tinib (Iressa) among EGFR mutation–positive patients. 

The last question is of particular in­terest, because gefitinib is not Food and Drug Association approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progres­sion-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefi­tinib or standard carboplatin and paclitaxel chemotherapy. 

IPASS demonstrated that EGFR mu­tation strongly predicted a lower risk of progression on gefitinib vs. chemother­apy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57). 

Similarly, in a pooled analysis of clin­ical outcomes of NSCLC patients who were treated with erlotinib, EGFR mu­tations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a dif­ference in overall survival among treated patients with and without EGFR muta­tions, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mu­tation in patients with NSCLC “confers a high level of resistance” to TKIs. 

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an associ­ation between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommen­dation for sequencing, as well as a rec­ommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lym­phoma kinase (ALK) fusion gene, Dr. Et­tinger said. 

“Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy,” he said, noting that the inves­tigational ALK-tar­geting drug crizotinib, in par­ticular, has demon­strated positive results in early studies of NSCLC patients with echinoderm mi­crotubule-associat­ed proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic ther­apy, patients with adenocarcinoma, large cell carcinoma, or NSCLC “not other­wise specified” who have an Eastern Co­operative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line thera­py should be treated with erlotinib, ac­cording to the NCCN guidelines. 

Alternatively, the guidelines state that gefitinib can be used in place of erlotinib “in areas of the world where it is avail­able.” 

For patients in whom the EGFR mu­tation is discovered during chemothera­py, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment.

For patients whose EGFR status is negative or unknown, even in the pres­ence of clinical characteristics that might be suggestive of a mutation (for exam­ple, female, nonsmoker, Asian race), con­ventional chemotherapy is recommended, Dr. Ettinger said. 

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the grow­ing clinical importance of molecularly defined subgroups of adenocarcinoma signals a “new era of personalized med­icine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy.” 

The implemen­tation of routine, simultaneous testing of multiple markers will likely be con­ducted on all patients prior to treat­ment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, includ­ing obtaining adequate tumor materi­al at the time of diagnostic biopsy and developing testing platforms “that si­multaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges.”

The updated NCCN Guidelines for NSCLC are posted at www.nccn.org. The ASCO PCO is posted at www.asco.org/ascov2/Practice+&+Guidelines/Guidelines/Provisional+Clinical+Opinion.

Dr. Ettinger has consultancy agree­ments with the a number of pharma­ceutical companies Dr. Keedy receives commercial research support from Ari­ad Pharmaceuticals, Ziopharm Oncolo­gy, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with a number of pharmaceutical companies. Dr. Doebele disclosed re­search funding from Lilly, ImClone Sys­tems, and Pfizer.