New Therapies Capitalize on Lung Cancer’s Molecular Vulnerabilities

Get Permission

Research reported at this year’s ASCO Annual Meeting attests to the tremendous molecular diversity of non–small cell lung cancer (NSCLC) and the power of appropriately selected treatment, according to Leora Horn, MD, of Vanderbilt University Medical Center, who presented data on molecular findings and targeted therapies in lung cancer at the Best of ASCO San Diego meeting. “We are moving beyond histology in selecting therapy for advanced NSCLC patients, and molecular testing should be considered in both squamous and nonsquamous NSCLC patients,” she recommended.

Squamous Cell NSCLC: Genetically Complex

Investigators with The Cancer Genome Atlas Project undertook comprehensive genomic characterization of squamous cell NSCLC tumors from 178 patients.1 Results showed a high rate of somatic mutations in these tumors compared with other common cancers, with only melanoma having a higher rate. The most commonly mutated genes included TP53, CDKN2A, and PTEN. Although changes in CDKN2A were associated with a loss of function in 72% of tumors, the mechanism of those changes (deletions, mutations, and methylations) differed across tumors.

“This is important to know because although you are getting the same phenotype, it may not all be affected by the same mechanism,” Dr. Horn commented. “An analogous situation would be [for] epidermal growth factor receptor (EGFR)…, where we know patients with EGFR mutations respond to therapies with EGFR tyrosine kinase inhibitors, whereas patients with EGFR amplification may not.”

Whole-genome sequencing showed an average of 165 somatic rearrangements per tumor, with marked heterogeneity between and within tumors. In addition, mRNA analysis identified four distinct phenotypes: primitive, classical, secretory, and basal. Potential therapeutic targets were identified for 11 genes showing alterations; in some cases, relevant agents are already in clinical trials.

“From these data, we know that squamous cell lung cancer is a complex disease. There are multiple different pathways affected that could lead to rational and hopefully successful drug development,” Dr. Horn commented.

“We need to consider not only the phenotype but also the method of gene alteration in selecting patients for clinical trials,” she added.

Afatinib in EGFR-mutated NSCLC Adenocarcinoma

The randomized phase III LUX-Lung 3 trial compared afatinib—an oral tyrosine kinase inhibitor targeting EGFR, the HER2 receptor, and other ErbB family receptors—with chemotherapy (pemetrexed [Alimta] and cisplatin) as first-line treatment in 345 patients with advanced lung adenocarcinoma harboring EGFR mutations.2 Compared with chemotherapy, afatinib conferred better median progression-free survival in the entire trial population (11.1 vs 6.9 months, HR = 0.58, P = .0004) and also in patients with the Del19 or L858R mutation of EGFR (13.6 vs 6.9 months, HR = 0.47, P < .0001).

The objective response rate was also better with afatinib overall (56% vs 23%, P < .001) and in the patients with Del19 or L858R mutations (61% vs 22%, P < .0001). Afatinib was associated with higher rates of certain grade 3/4 adverse events, but generally better scores for quality of life.

“First-line afatinib, although we should not be comparing across clinical trials, does not appear to be more effective than other EGFR [tyrosine kinase inhibitors],” Dr. Horn maintained. “What this means right now is that afatinib is another potential option … for first-line therapy for EGFR mutation–positive NSCLC,” she said.

“The bigger issue in my mind is acquired resistance, as all of these patients have a progression-free survival of approximately 1 year,” she added. “So acquired resistance remains a major issue regardless of the EGFR [tyrosine kinase inhibitor] administered.”

Crizotinib in NSCLC with ROS1 Rearrangement

In an expansion cohort of a phase I trial, investigators assessed the clinical activity of crizotinib (Xalkori)—an oral tyrosine kinase inhibitor targeting MET, ALK, and ROS—in 15 patients with advanced NSCLC harboring the ROS1 gene rearrangement.3 The overall response rate was 57%, with some patients experiencing dramatic regression of their pulmonary infiltrates.

“Right now, these data are very impressive but premature, with only 15 patients enrolled on the study,” Dr. Horn commented. “We need to consider ROS1 testing in select NSCLC cohorts and consider enrolling these patients on the ongoing clinical trial.”

Docetaxel vs Erlotinib in EGFR Wild-type NSCLC

The randomized phase III TAILOR trial compared erlotinib (Tarceva) with docetaxel as second-line therapy in 219 patients with NSCLC having wild-type EGFR.4 Patients in the docetaxel group had a higher response rate (14% vs 2%, P = .004) and disease control rate (42% vs 23%, P = .007).

Docetaxel also conferred better median progression-free survival (3.4 vs 2.4 months; HR = 0.69; P = .014), with similar benefit across patient subgroups. “Interestingly, KRAS did not seem to be a prognostic factor in second-line therapy in this cohort of NSCLC patients,” Dr. Horn observed.

“Based on data from TAILOR and the IPASS trial, where patients who were EGFR wild-type did better when treated with chemotherapy, we know that chemotherapy is preferred over EGFR [tyrosine kinase inhibitors] in patients with NSCLC who are EGFR wild-type,” she concluded.

Anti–PD-1 Antibody in Advanced NSCLC

A phase I trial assessed the activity and safety of immune therapy with an antibody to PD-1 (a protein that suppresses antitumor activity) in 296 patients with various tumor types, 122 of whom had advanced NSCLC.5 The trial did not identify a maximum tolerated dose, and there was no association between drug dose and the rate of adverse events.

The rate of grade 3/4 drug-related adverse events was 14% in patients overall and 8% in patients with NSCLC. The rate of grade 1/2 pneumonitis was 2% in patients overall and 3% in patients with NSCLC; three patients developing pneumonitis died.

The overall response rate was 18% in patients with NSCLC, with some patients having dramatic disease regression. The 24-week rate of progression-free survival was 26%.

“This agent is the first immune therapy drug with activity in NSCLC patients. The benefit appears to be durable and was seen in both squamous and nonsquamous NSCLC,” Dr. Horn commented. “The findings of this study support the importance of the PD-1 pathway in NSCLC across different histologies.”

She noted that additional published data showed a correlation between expression of the ligand of PD-1 (PD-L1) on tumor cells and the response to the antibody.6 “PD-L1 may turn out to be another marker where we can select patients who will benefit from therapy with either an anti–PD-1 antibody or an anti–PD-L1 antibody,” she proposed.

“Based on these data, they have gone straight from phase I to phase III,” with two large randomized trials opening in lung cancer, Dr. Horn noted. ■

Disclosure: Dr. Horn is an unpaid advisor for Astellas, Genentech, and OSI.


1. Govindan R, Hammerman PS, Hayes DH, et al: Comprehensive genomic characterization of squamous cell carcinoma of the lung. 2012 ASCO Annual Meeting. Abstract 7006. Presented June 4, 2012.

2. Yang JC-H, Schuler MH, Yamamoto N, et al: LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. 2012 ASCO Annual Meeting. Abstract LBA7500. Presented June 4, 2012.

3. Shaw AT, Camidge DR, Engelman JA, et al: Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. 2012 ASCO Annual Meeting. Abstract 7508. Presented June 2, 2012.

4. Garassino MC, Martelli O, Bettini A, et al: TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR. 2012 ASCO Annual Meeting. Abstract LBA7501. Presented June 4, 2012.

5. Brahmer JR, Horn L, Antonia S, et al: Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC). 2012 ASCO Annual Meeting. Abstract 7509. Presented June 2, 2012.

6. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.

Related Articles

SIDEBAR: Molecular Testing Requires Planning at Time of Biopsy

The molecular analysis of lung cancer patients is becoming more and more complex,” and clinicians therefore need to consider any additional tissue requirements upfront, Dr. Horn commented.

At Vanderbilt University, testing for EGFR, KRAS, and eight other mutations is done using the Lung SnaPshot...

SIDEBAR: Should EGFR Tyrosine Kinase Inhibitors Be Continued Beyond Progression?

It is not yet clear if it is beneficial to continue first-line EGFR tyrosine kinase inhibitors in patients with EGFR-mutated lung cancer who experience progression and are started on chemotherapy, according to Dr. Horn. Two trials, one in Asia (looking at gefitinib [Iressa]) and one in North...