Gina Columbus, Beth Fand Incollingo, Tony Hagen

Being an oncologist treating non-small cell lung cancer these days is kind of like going on an amusement park ride: You need to hang on tightly.

David Gandara has experienced that firsthand.

“In lung cancer, things have never moved at such a fast pace,” Gandara, M.D., told a roomful of medical professionals when he discussed the changing landscape of treatment for the disease during the 2016 International Lung Cancer Congress held in August in Huntington Beach, California.

In fact, Gandara, who directs the Thoracic Oncology Program at the UC Davis Comprehensive Cancer Center, said that treatment plans for advanced squamous and nonsquamous non-small cell lung cancer (NSCLC) drawn up by his staff in 2014 are already outdated. Specifically, chemotherapy has become less of a focus.

In 2014, Gandara’s team suggested that targeted drugs known as tyrosine kinase inhibitors (TKIs), which hone in on and disable mutations that drive cancer, should be given as the first line of defense to patients whose disease expressed EGFR and ALK mutations, with chemotherapy used only after that. But for lung cancers that didn’t express those mutations, the options were chemotherapy with Avastin (bevacizumab), a targeted drug that disables the blood vessels that feed tumors, followed by chemotherapy and the targeted drug Tarceva (erlotinib) as maintenance therapy.

While chemotherapy still has a role, doctors now much more frequently turn to immunotherapies to treat these patients. Chemotherapy is used first only in patients whose cancers don’t express mutations that indicate they are likely to benefit from TKIs or immunotherapies known as checkpoint inhibitors.

This illustrates how immunotherapies have established themselves in just a few years, Mark W. Kris, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, told 

“Last year, people received chemotherapy up front if they didn’t have an obvious (genetic) driver (of their cancer). If chemotherapy stopped working or had to be stopped, people immediately went to another chemotherapy,” said Kris. “In 2016, every single patient [in my practice] gets immunotherapy.”

But with the fast pace of evolution in the treatment and handling of advanced NSCLC over the past few years, some gray areas have become apparent. Doctors and scientists are working to fine-tune their understanding of how best to apply immunotherapies and targeted agents in lung cancer, and of how to incorporate testing for biomarkers that might predict how well, or whether, individual patients will respond to these drugs.

FDA-approved immunotherapies, such as Opdivo (nivolumab), Keytruda (pembrolizumab) and Tecentriq (atezolizumab), have demonstrated long-lasting benefits in lung cancer.

“People have tried to find a way to rev up the immune system to fight all cancers for more than 100 years,” Kris said. “Up until now, it has been a goal or a dream, and only recently are we able actually to deliver on that for patients with lung cancer.”

The immunotherapies generating such excitement in lung cancer are checkpoint inhibitors. These agents target the PD-1/PD-L1 or CTLA-4 signaling pathways, which are involved in keeping the immune system under control so that it doesn’t attack healthy tissue. Immunotherapies take the brakes off the immune system, helping it to recognize cancer and move into high gear to fight the disease. Opdivo and Keytruda are checkpoint inhibitors that target PD-L1 and PD-1, respectively. Tecentriq, approved in October for certain patients with metastatic NSCLC, targets PD-L1.

“What we have seen is that agents that target PD-1/PD-L1, and now agents that target CTLA-4, are very helpful in leading to dramatic benefits for patients with lung cancer,” Kris said. “There is very clear evidence that, particularly for Opdivo and Keytruda, they improve rates of shrinkage and improve duration of survival — which is an extremely impressive result &mdash; over standard chemotherapy (docetaxel).”

“Equally as important to those benefits in outcome are the benefits in terms of severe side effects, because approximately half of patients who receive docetaxel get some kind of a severe side effect,” Kris added. “Now, only about 10 percent of patients who receive immunotherapies get those side effects, so it has everything going for it.”

The path forward is clear, Kris said: Immunotherapies are going to be given first, and chemotherapy will follow if disease relapses or progresses.

In addition, immunotherapy combinations are on the horizon. Combining PD-1 or PD-L1 inhibitors with anti-CTLA-4 immunotherapies, such as Yervoy (ipilimumab), may bring better results, Kris said.

“At the 2016 Annual Meeting of ASCO (the American Society of Clinical Oncology), there was one presentation by Matthew Hellmann, M.D. (of Memorial Sloan Kettering Cancer Center) regarding the CheckMate 012 trial with Opdivo and Yervoy,” Kris said. “They were comparing it to patients in these same trials who received (only) Opdivo, (and those in the combination group had) higher rates of response, longer durations of response and better survival.”

Also, while Yervoy on its own tends to cause more and harsher side effects than PD-1/PD-L1 inhibitors, Kris noted that, “by adjusting the dosages and schedules of Yervoy and Opdivo, results showed very good tolerance, and truly almost the same degree of side effects with the combination as with Opdivo alone.”

The trial results were also compelling for other reasons, Kris said.

“What many people thought was the most amazing finding,” he said, “was that a number of people on that trial had no growth of their cancer after years of treatment. Some of them have come to surgery to remove what was left after years of treatment on those studies, and what they found is nothing — just scar tissue. Therefore, the benefits in the short term, in terms of response and fewer side effects and the chance for long survival, make these regimens very appealing.”

As immunotherapies evolve into their role in treating lung cancer, targeted agents, such as Avastin, Cyramza (ramucirumab) and Portrazza (necitumumab), among others, are also advancing the field.

Avastin works by stopping the growth of blood vessels that feed a tumor; Cyramza targets a VEGF gene mutation and stops it from driving the cancer; and Portrazza targets EGFR and slows or stops its contribution to lung cancer.

These kinds of drugs, and many immunotherapies, too, seem to work best in people with specific gene mutations, and multiple studies are being conducted to find out who, exactly, can benefit from them.

Linnea Olson became a pioneer in that effort after she was diagnosed with lung cancer in April 2005 at the age of 45, after two years of being misdiagnosed with asthma.

The 5 cm mass on her left lung was difficult to treat, and, in October 2008, she was told she’d reached the end of her therapy options. That was when she joined her first clinical trial.

“This opportunity arose after it was discovered that I had an ALK mutation, and on Oct. 1, 2008, I became the fourth person in the world with NSCLC to take crizotinib, now marketed as Xalkori,” Olson said. “This was a phase 1 clinical trial, and my expectations were low — the only other participant at my hospital had died within weeks of starting trial, in part because of side effects from the experimental therapy.”

But given only months to live, Olson decided it was worth the leap of faith, which paid off when she saw a 70 percent reduction in tumor burden. “I went from preparing for my death to living again. However, I knew that this did not represent a cure.”

Olson went on to be enrolled in two more phase 1 clinical trials — a trial for the ALK inhibitor Zykadia (ceritinib) and another for lorlatinib, a still-investigational drug that targets both ALK and ROS1 mutations.

“I consider clinical trials my lifeline,” she said. “I would definitely encourage other patients to explore this option. Sometimes it is the best course of action and, in my own case, offered me an avenue just as it seemed I’d come to the end of my journey.”

In the search for meaningful biomarkers, Portrazza was at the heart of one defining trial in 2015. The SQUIRE trial tested the effectiveness of chemotherapy with or without Portrazza in advanced squamous NSCLC, and its results, which Gandara called “deceptively modest,” showed that overall survival (OS) was 11.5 months in the Portrazza arm versus 9.9 months with chemotherapy only.

One thing that set this trial apart was that many previous trials had failed to show any OS advantage from targeted agents, Gandara said. Just as important, he said, was that the SQUIRE results helped to clarify the potential of biomarker strategies in squamous NSCLC. For EGFR-positive patients, OS widened to 12.6 months in the combination arm of the trial, versus 9.2 months for the standard gemcitabine-cisplatin chemotherapy group.

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 3 CheckMate trials (017 and 057) involving Opdivo versus docetaxel showed an advantage with the PD-L1 inhibitor for both squamous and non-squamous NSCLC patients; however, at the 12-month point, the OS rate was significantly better for non-squamous tumors (51 percent) than for squamous (42 percent) — “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 Opdivo was independent of PD-L1 expression, whereas among non-squamous patients, OS directly correlated with PD-L1 status. In the KEYNOTE 010 trial, Keytruda improved OS versus docetaxel in patients with advanced NSCLC who had previously been treated with platinum-based chemotherapy. Moreover, in the strongly PD-L1-positive subgroup, progression-free survival also improved with Keytruda versus chemotherapy, once again strengthening the evidence supporting the potential for biomarker guidance in NSCLC, Gandara said.

Finally, the KEYNOTE-024 trial evaluating Keytruda versus chemotherapy as first-line treatment for advanced NSCLC removed all doubt about the value of high-expression PD-L1 as a “smoking-gun” biomarker, Gandara said.

Reported in June, the results of the trial showed that frontline Keytruda improved OS versus chemotherapy in patients with NSCLC who had high levels of PD-L1 expression. Keytruda was also shown to extend progression- free survival (PFS) in the first-line NSCLC setting. Gandara predicted that “this trial will alter the standard of care in first-line therapy of the great majority of patients with advanced NSCLC.”

He said that a question now demanding attention is whether it’s wise to continue the use of checkpoint inhibitors after first-line treatment and disease progression. “In other words,” he asked, “is there something there that will continue to benefit patients even though they look like they’ve progressed?”

Gandara 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 Keytruda, followed by carboplatin-pemetrexed chemotherapy with or without Keytruda as a second-line treatment.

Backed by new evidence, updated guidelines have added actionable biomarkers and more drugs to the list of acceptable treatment paths. In lung adenocarcinoma, targeted drugs like Cabometyx (cabozantinib) for those with RET mutations and Xalkori for those with ROS1 mutations are producing impressive response rates, although these mutations are rare, so there’s a limited population of patients who can benefit from these, he said.

Figuring out how best to use new drugs like Tagrisso (osimertinib), which targets a specific EGFR mutation that causes resistance to EGFR inhibitors like Tarceva, also should become a priority, he advised.

“Can we do combinations to make this drug more effective?” he asked. “We need to think this way.”

He added that it is no longer necessary to test for a huge number of genes in order to make it worthwhile to use multiplexing and next-generation genome sequencing. “I think we have to convince (private insurers), CMS (Medicare/ Medicaid) — everybody &mdash; that we are at that point where it is cost-effective to use next-generation sequencing,” he said. To aid in that kind of testing, new tools have materialized virtually overnight, Gandara noted, including “liquid biopsies” that analyze blood instead of tissue for gene mutations and other tumor markers.

Gandara would 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-positive cancer,” he said.

“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.”

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