Positioning Targeted and Immunotherapy-Based Approaches in Lung Cancer

Get Permission

Fadlo Khuri, MD, FACP

Suresh S. Ramalingam, MD

If you know you have a driver mutation, you go with targeted therapy. But without a known mutation, in the second-line setting, you go with nivolumab, which is dramatically superior to docetaxel.

—Fadlo Khuri, MD, FACP
Immunotherapy is going to have a stronger impact on lung cancer than targeted treatment has had so far. Immunotherapy improves survival, and this cannot be said for targeted agents.

—Suresh S. Ramalingam, MD

With immunotherapy changing the face of lung cancer, is there still a place for targeted therapy? Two experts from Emory University debated this issue at the 2015 Debates and Didactics in Hematology and Oncology Conference held in Sea Island, Georgia. Fadlo Khuri, MD, was recently named President of the American University of Beirut in Lebanon, and Suresh S. ­Ramalingam, MD, is Professor and Director of Medical Oncology at Emory.

Targeting Driver Mutations

“In my view,” Dr. Khuri maintained, “when you have highly characterized genomic drivers, you are going to go with genomically targeted therapy.”

Lung cancer exhibits at least three targetable mutations, at least one of which is harbored by almost two-thirds of patients with adenocarcinomas. Half or more of these patients will respond to targeted agents, with a duration of benefit that can be “quite striking,” Dr. Khuri said.

Numerous benefits remain unique to targeted agents, he said, including the opportunity to target specific drivers of oncogene-addicted tumors, high response rates, reliability and availability of biomarkers in genomic testing, a favorable cost-benefit ratio, and an understanding of mechanisms of resistance.

The prognosis of non–small cell lung cancer (NSCLC) dramatically changed with the discovery of mutations in the epidermal growth factor (EGFR). The ability to target such tumors with tyrosine kinase inhibitors led to a “sea change” in the management of EGFR-mutated patients. EGFR inhibitors became and remain the first-line standard of care, he said.

The emergence of resistance has been the Achilles heel of targeted therapy, but drugs in development are tackling that problem, especially by overcoming the hallmark T790M mutation. About half the patients whose disease progresses demonstrate this alteration.

“We now have impressive data showing that we understand this mutation, its biology, and its prognosis, and we have developed treatments that target T790M,” he said.

Patients with the T790M mutation almost invariably respond to the third-generation EGFR inhibitor AZD9291. In a study of 138 mutation-positive patients, the disease control rate was 95%.1 Similar agents are in development, including rociletinib (CO-1686), which has demonstrated a disease control rate of 93% and produced responses in almost 60% of T790M-mutated patients.2

The ALK fusion gene represents the other “success story” of targeted management. Showing striking activity (doubling of progression-free survival) in the 5% of patients with NSCLC who have this alteration, the ALK inhibitor crizotinib (Xalkori) was rapidly approved.3

Resistance to crizotinib is also being tackled as more is learned about the mechanisms of resistance to ALK inhibitors, which differ from those observed with EGFR inhibitors. Third-generation ALK inhibitors in development, including ceritinib (Zykadia) and alectinib, are effective in more than 50% of crizotinib-treated patients. The dual ALK/EGFR inhibitor AP26113 is also active in patients with secondary resistance to ALK, he noted.

BRAF, the third driver mutation that can be targeted, is identified in 1% to 2% of patients. Monotherapy with dabrafenib (Tafinlar) yielded a disease control rate of 56% at 12 weeks and a median duration of response of 11.8 months in previously treated patients.4 It may be even more effective when combined with trametinib (Mekinist), Dr. Khuri said.

A Place for Immunotherapy

Since targeted therapy is limited to mutation subsets, there is a place for immunotherapy, especially as second-line therapy, Dr. Khuri acknowledged. “If you know you have a driver mutation, you go with targeted therapy. But without a known mutation, in the second-line setting, you go with nivolumab [Opdivo], which is dramatically superior to docetaxel,” he said.

“No question, there is no more exciting science than cancer immunotherapy. Especially with combination immunotherapy, we may see dramatic, durable responses,” he acknowledged.

However, Dr. Khuri pointed out that the benefits may be accompanied by more toxicity (especially with combinations) than is seen with targeted therapy. “One of the most evident toxicities is to the bank account!” he added.

For a median progression-free survival of 6.9 months, nivolumab monotherapy costs more than $100,000. For a median progression-free survival of 11.4 months, the cost approaches $300,000, according to some calculations.

“In my view, this is probably more than the market can bear,” Dr. Khuri commented. Coupled with a 20% copay for patients, “this will be unsustainable.”

Dr. Ramalingam pointed out that as good as targeted therapy is, this approach has never cured a patient with lung cancer. “Immunotherapy is going to, by far, have a stronger impact on lung cancer than targeted treatment has had so far,” he maintained. “Immunotherapy improves survival, and this cannot be said for targeted agents.”

In addition, he added, immunotherapy can be applied to all-comers, and that unlike targeted therapy, its effect is not preferential to persons who have a little to no smoking history (ie, not the average patient). Immunotherapy addresses the “garden variety lung cancer,” which is smoking-derived tumors with high mutational burdens, he indicated.

Dr. Ramalingam further reminded listeners that although 65% of patients have a driver mutation, 25% of them will be in KRAS, “which still begs for a treatment option.” Targeted treatments, he pointed out, “are therefore used in a small percentage of our patients.”

Additional obstacles to the use of targeted therapies are the emergence of resistance, for which current options are limited, and their failure to be effective earlier in the disease course. However, targeted agents do have the edge over immunotherapy in terms of response rates, he acknowledged, but added that when patients do respond to immunotherapy, their benefits can be durable.

Survival Benefits With Immunotherapy

“We also now have overall survival data showing immunotherapy to be superior,” said Dr. Ramalingam.

In a phase I study of nivolumab in refractory NSCLC,5 2-year survival was 24%, and at 3 years, 18% of heavily pretreated patients remained free from progression, he noted. “To be alive 3 years later is very exciting for patients who have run out of options,” added Dr. Ramalingam.

In the phase III CheckMate 017 trial in previously treated squamous cell carcinoma, nivolumab significantly improved overall survival over docetaxel in the second-line setting.6 The hazard ratio of 0.59 compares favorably with that seen with targeted agents vs chemotherapy in the front line, “and this is second line,” he added. “First-line data will be out in a year or so, and if this is a sign of what’s to come, we are in for an exciting time.”

The possibility of long-term survival is further illustrated by a study led by Dr. Ramalingam of nivolumab in refractory patients with squamous cell carcinoma.7 Although the response rate was only 14%, almost all responders had ongoing responses, whether or not they continued on nivolumab.

“That tells us the power of immunotherapy,” he commented. “With targeted therapy, the median progression-free survival is 10 to 13 months. With these patients, we haven’t reached the median duration of response.”

Activity in nonsquamous histology also has shown that the anti–PD-1 (programmed cell death protein 1) antibodies are not “one-trick ponies,” he continued. Although it yielded a slightly lower hazard ratio (0.73), nivolumab improved survival over docetaxel as second-line treatment of nonsquamous patients in the phase III CheckMate 057 study.8 “These two trials show that immunotherapy trumps targeted therapy in the second line,” he maintained.

Beyond Nivolumab

Strong data are also emerging for anti–PD-1/PD-L1 (its ligand) agents other than nivolumab. In the phase II POPLAR trial, atezolizumab significantly improved overall survival vs docetaxel in patients with strong PD-L1 expression; the response rate was 38%, and median overall survival was not reached.9

Although such findings suggest that PD-L1 expression may help select patients, noted Dr. Ramalingam, “These drugs work even in PD-L1–negative patients. Their outcomes are at least as good as with chemotherapy, and we need to bear this in mind in terms of selecting patients.”

Impressive outcomes were also achieved among PD-L1–positive patients receiving pembrolizumab (Keytruda) in KEYNOTE-001.10 In updated results, high expressers (≥ 50% staining) had a response rate of 52%, a median progression-free survival of 12.5 months, and a median overall survival that had not been reached.

The anti–PD-1/PD-L1 agents may be even more effective in combination with other agents. In early-phase studies, pembrolizumab plus chemotherapy has yielded a disease control rate of 100%, with relatively good tolerability, he added.

In conclusion, Dr. Ramalingam maintained that immunotherapy offers the best chance of long-term survival in advanced lung cancer and a means of changing the biology of this disease. ■

Disclosure: Dr. Khuri reported no potential conflicts of interest. Dr. Ramalingam has served on advisory boards for and has received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck, and Genentech.


1. Jänne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689-1699, 2015.

2. Sequist LV, Soria JC, Goldman JW, et al: Rociletinib in EGFR-mutated non-small cell lung cancer. N Engl J Med 372:1700-1709, 2015.

3. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.

4. Planchard D, Kim TM, Mazières J, et al: Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer: A multicenter, open-label phase II trial (BRF113928). 2014 ESMO Congress. Abstract LBA38_PR. Presented September 29, 2014.

5. Brahmer J, Horn L, Antonia S: Nivolumab in patients with non-small cell lung cancer: Overall survival and long-term safety in phase 1 trial. 2013 IASLC 15th World Conference on Lung Cancer. Abstract MO 18.03.

6. Spigel DR, Reckamp KL, Rizvi NA, et al: A phase III study (CheckMate 017) of nivolumab vs docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8009. Presented May 29, 2015.

7. Rizvi NA, Mazières J, Planchard D, et al: Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol 16:257-265, 2015.

8. Paz-Ares, L, Horn L, Borghaei H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109. Presented May 29, 2015.

9. Spira AI, Park K, Mazières J, et al: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). 2015 ASCO Annual Meeting. Abstract 8010. Presented May 29, 2015.

10. Garon EB, Rizvi NA, Hui R et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.