Optimal Therapy Sequence Continues to Evolve for Advanced NSCLC

The past few years have seen rapid evolution in the treatment and handling of advanced non–small cell lung cancer, prompting questions on how to optimize immunotherapies and targeted agents as well as incorporate biomarker testing.

David R. Gandara, MD

The past few years have seen rapid evolution in the treatment and handling of advanced non—small cell lung cancer (NSCLC), prompting questions on how to optimize immunotherapies and targeted agents as well as incorporate biomarker testing, according to David R. Gandara, MD.

“In lung cancer, things have never moved at such a fast pace,” said Gandara during his presentation on the changing landscape of lung cancer treatment at the 2016 International Lung Cancer Congress held August 4-6, 2016 in Huntington Beach, California.

Gandara, who directs the Thoracic Oncology Program at the UC Davis Comprehensive Cancer Center, said that treatment plans for advanced squamous and nonsquamous NSCLC drawn up by his own staff in 2014 are now outdated.

Those guidelines suggested first-line therapy with tyrosine kinase inhibitors (TKI) for EGFR-mutated and ALK-positive patients and chemotherapy in the second line. For non-oncogene driven cancers, the options were chemotherapy with bevacizumab, replaced by chemotherapy and erlotinib as maintenance or second-line therapy.

Today, however, checkpoint inhibitors are much more prevalent, with chemotherapy used frontline only when PD-L1 expression is negative, illustrating how these agents have established themselves in just a few years, Gandara said.

And, on the targeted therapy front, “Now we have the third-generation TKI osimeritinib for EGFR, we have ramucirumab, and we have necitumumab for squamous cell lung cancer—in first line. We have afatinib as a possible agent in second- or third-line therapy for squamous cell lung cancer.”

One dramatic turning point in NSCLC was the SQUIRE trial (chemotherapy plus or minus necitumumab in advanced squamous NSCLC)1, which in 2015 yielded results that were deceptively modest, Gandara noted, with overall survival (OS) of 11.5 months for the necitumumab arm versus 9.9 months with chemotherapy only (HR, 0.84; 95% CI, 0.74-0.96). What set this trial apart was that many previous trials had failed to show any OS advantage from targeted agents, Gandara said. “Some of them were not just negative. The patients who got the targeted therapy actually had shorter survival than the ones who just had chemotherapy.”

An analysis of SQUIRE results with fluorescence in situ hybridization (FISH) testing helped to clarify the potential of biomarker strategies in squamous NSCLC, however. For EGFR-positive patients, OS widened to 12.6 months on chemotherapy plus necitumumab, versus 9.2 months for the standard gemcitabine-cisplatin group (HR, 0.70; 90% CI, 0.52-0.96).

Gandara said that this evaluation showed “that we could potentially identify a biomarker strategy for this class of agents which would make them more robust in the treatment of squamous cell lung cancer, so I hope that we will be able to pursue this and find out which patients are most likely to benefit.”

Two phase III CheckMate trials (017 and 057) involving nivolumab versus docetaxel showed an advantage with the PD-L1 inhibitor for both squamous and non-squamous NSCLC patients2,3; however, at the 12-month point, the OS rate was significantly better for non-squamous tumors (51%) than for squamous (42%)—“telling us once again that squamous cell lung cancer and non-squamous cell lung cancer are very different diseases,” Gandara noted.

Further analysis of these two trials found that in squamous NSCLC, the survival benefit from nivolumab was independent of PD-L1 expression, whereas among non-squamous patients, OS directly correlated with PD-L1 status.

In the KEYNOTE 010 trial, pembrolizumab improved OS versus docetaxel in patients with advanced NSCLC.4 Moreover, in the strongly PD-L1—positive subgroup, progression-free survival also improved with pembrolizumab versus chemotherapy, once again strengthening the evidence supporting the potential for biomarker guidance in NSCLC, Gandara said.

The KEYNOTE-024 trial5 evaluating pembrolizumab vs chemotherapy in first-line advanced NSCLC removed all doubt about the value of high-expression PD-L1 as a “smoking-gun” biomarker, Gandara said, and he predicted that “this trial will alter the standard of care in first-line therapy of the great majority of patients with advanced NSCLC).”

Gandara said that among the questions that now need to be addressed, is whether it’s wise to continue use of checkpoint inhibitors after first-line treatment and disease progression. “In other words, is there something there that will continue to benefit patients even though they look like they’ve progressed?”

He pointed to a joint ECOG-SWOG proposal for an advanced non-squamous NSCLC trial that hopes to shed light on this issue. Patients would be randomized to first-line pembrolizumab, followed by carboplatin-pemetrexed with or without pembrolizumab in the second line.

New tools available for disease testing have materialized virtually overnight, Gandara said. “We also did not anticipate that we might in 2016 be debating the merits of plasma DNA or even plasma RNA expression to complement or perhaps replace the use of tissue,” he said.

Backed by new evidence, updated guidelines have added actionable biomarkers and more drugs to the list of acceptable treatment paths. In lung adenocarcinoma, drugs like cabozantinib for RET and crizotinib for ROS1 are producing impressive response rates, but you have to work harder to find the opportunities to use drugs like these, he said.

And, he added, it is no longer necessary to test for a huge number of genes to use multiplexing and next generation sequencing (NGS) economically, Gandara said. “I think we have to convince [private insurers], CMS—everybody—that we are at that point where it is cost-effective to use NGS.”

Figuring out how to use new drugs like osimertinib to best advantage also should become a priority. “Can we do combinations to make this drug more effective? We need to think this way.” Gandara would also like to see more attention paid to the merits of repeat biopsies to guide treatment processes more accurately. This is because tumor biology has a tendency to evolve, he explained.

“You find an oncogene, you treat, and you re-biopsy on progression. You determine a new therapy, you retreat, and when there is progressive disease, you re-biopsy again. I have some patients now who are on their third or fourth re-biopsy with an oncogene cancer.

“Now there are strategies in place where we can do what would be called ‘biomarker switch therapy,’ where you monitor for a mechanism of resistance, and you switch [patients] to an alternative drug—not when the CT scan turns bad, but based on a plasma biomarker.” He cautioned, however: “These concepts have to be proven in randomized trials.”


  1. Thatcher N, Hirsch FR, Luft AV,et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase III trial. Lancet Oncol. 2015;16(7):763-774.
  2. Brahmer J1, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135.
  3. Borghaei H1, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-1639.
  4. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550.
  5. Garon EB, Rizvi N, Hu R, et al. Pembrolizumab for the treatment of non—small cell lung cancer. N Engl J Med. 2015;372:2018-2028.


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