Novel Therapies, Strategies in Development for NSCLC

Corey Langer, MD

The treatment landscape for patients with non-small cell lung cancer (NSCLC) is poised to undergo dramatic changes, as novel immunotherapies, second-generation targeted therapies, and new maintenance strategies continue to show promise in clinical trials.

As these multiple advances move forward, there remain several unanswered questions. Historically, immunotherapeutic approaches have not been effective in lung cancer. However, early-phase results for antibodies against the immune checkpoints programmed death-1 (PD-1) and its ligand (PD-L1) have sparked great enthusiasm in the lung cancer community. Additionally, as multiple next-generation ALK and EGFR inhibitors progress rapidly toward approval, it remains unclear where they will fit with current treatments, and whether there is an optimal sequence for patients with NSCLC.

To explore these conundrums, Corey J. Langer, MD, led a recent OncLive Peer Exchange® roundtable discussion entitled “Improving Clinical Outcomes in NSCLC.” This discussion explored frontline treatment approaches and evolving maintenance strategies for patients with advanced NSCLC.

Immune Checkpoint Inhibition

A variety of therapies are in development in lung cancer that target immune checkpoints. As a result of the efficacy seen with these agents, checkpoint inhibitors are being explored across a number of settings for patients with NSCLC, including in earlier stage, locally advanced NSCLC and in the adjuvant setting.

“I think this class of drugs has generated considerable enthusiasm within the thoracic community, for good reason,” said Benjamin P. Levy, MD. “I think, historically speaking, immunotherapeutic approaches in lung cancer have failed, and this class of drugs has ushered in a new era, working by suppressing inhibitory signaling in the immune system, basically uncamouflaging the tumor cell and allowing the T cells to recognize it.”

Targeting PD-1

Results for the anti-PD-1 inhibitor nivolumab in heavily pretreated patients with NSCLC were presented at the World Conference on Lung Cancer in October 2013.¹ This trial enrolled 129 patients with NSCLC and demonstrated an overall response rate (ORR) of 17%, with a greater than 18-month median duration of response (DOR). The median overall survival (OS) for all dosages and histologies was 9.6 months. At the 3-mg/kg dosage that will be explored in phase III trials, the median OS increased to 14.9 months.

In general, the toxicity profile for nivolumab was manageable, with less than 5% of patients experiencing adverse events of grade 3/4 severity. However, these agents still do have toxicity, the panelists cautioned, but overall they are very well tolerated.

In addition to nivolumab, the PD-1 immune checkpoint inhibitor MK-3475 also demonstrated activity in highly pretreated patients with NSCLC.² In this investigation, the ORR was 21% by RECIST criteria with an initial immune-related response of 24%. The DOR with MK-3475 was durable, although not yet reached in the analysis.

Targeting PD-L1

A similar approach to targeting PD-1 directly targets the associated ligand, PD-L1. The lead treatment in this space, MPDL3280A, currently has less data than the PD-1 inhibitors but seems to have similar efficacy and safety. In data presented at the World Conference on Lung Cancer, the ORR with MPDL3280A was 23%.³ PDL1 inhibition appeared effective, regardless of smoking status, KRAS status, or the number of prior therapies received. The only significant indicator of response in this study was PD-L1 status.

MODERATOR:

Corey J. Langer, MD

Director of Thoracic Oncology

University of Pennsylvania Abramson Cancer Center

Philadelphia, PA

PANELISTS:

Mark G. Kris, MD

Professor of Thoracic Oncology

Memorial Sloan Kettering Cancer Center

New York, NY

Benjamin P. Levy, MD

Director of Thoracic Medical Oncology

Mount Sinai Beth Israel

New York, NY

Mark A. Socinski, MD

Professor of Medicine

University of Pittsburgh

Pittsburgh, PA

Heather A. Wakelee, MD

Associate Professor of Medicine (Oncology)

Stanford University School of Medicine

Stanford, CA

Given these findings, the lead biomarker under exploration for the immune checkpoint inhibitors is PD-L1. At this point, separate assays are being utilized along with each agent, making cross comparison between studies difficult.

In an analysis presented at the 2014 American Association for Cancer Research (AACR) Annual Meeting, a PD-L1 level of greater than 50%, as measured by immunohistochemistry (IHC), was determined to be the best cutoff for differentiating between positive and negative treatments for patients with NSCLC receiving MK-3475. Based on this cutoff, after 6 months of treatment the OS rate was 89% for patients with high levels of PD-L1 compared with 33% for those with low levels. The progression-free survival (PFS) rates were 67% versus 11%, for high and low PD-L1 expression, respectively.⁴

“With these drugs there’s a lot of work being done trying to figure out a good biomarker. And the PD-L1 expression is the leading contender for that,” said Heather A. Wakelee, MD. “However, each company is developing its own PD-L1 antibody, and so it’s hard to know which one is going to be the truth, the gold standard. In all of the places where this has been looked at, all of the different compounds, the response rate is higher when the PD-L1 expression is positive.”

As immunotherapeutics, the response seen with these agents is dependent on the number and activity of T cells. However, these treatments also possess characteristics similar to targeted therapies, since their efficacy is impacted by the presence of PD-L1.

“You then have the situation where you have T cells but no PD-L1, PD-L1 but not T cells, and then you have neither. And, as you go down that, you see very different responses and that makes a lot of sense to me,” said Mark G. Kris, MD. “So this is probably targeted therapy, and to make it work you need PD-L1 and you need T cells.”

The leading challenge with this approach will be the difficulty in obtaining an accurate biopsy from a small metastatic lesion, specifically in light of tumor heterogeneity. This challenge draws into question the accuracy of selecting patients based on PD-L1 findings from metastatic lesions. As a result, some of the panelists believe it is too early to exclude patients from treatment with PD-1 and PD-L1 inhibitors based only on PD-L1 expression by IHC whereas others believe this approach would accelerate the approval path for these treatments.

“If your interest is getting new therapies to our lung cancer population, I think [selecting for PD-L1] is the most appropriate strategy and then worry about the rest of the population once you have the drug out there and available,” stated Mark A. Socinski, MD.

Phase II/III Trials

In addition to the promising data from phase I trials, several randomized phase II/III clinical trials are exploring immune checkpoint inhibitors as treatment for patients with NSCLC. The trials are exploring these therapies in the first- and second-line settings in combination with chemotherapy and targeted therapies or as single agents. Additionally, research will continue to focus on the discovery of optimal markers, side effect management, and sequences for these agents.

“The history in lung cancer for positive phase III trials has been rather sobering over the years,” Socinski pointed out. “We need to wait for the results of the phase III trials to see how they fit.”

Early trials have proved that immune checkpoint inhibitors are a reasonable option for patients with NSCLC; however, whether they will replace a standard therapy or work in combinations remains to be determined. Since these agents have a specific effect on the immune system, the discovery of an ideal marker may be integral to the future of this treatment strategy.

“I think the drugs have proved themselves already as another option for our patients. I think there’s no doubt about that,” Kris said. “What they’re going to replace, I don’t know, but I think they’re going to be added to it.”

Next-Generation ALK Inhibitors

Crizotinib

The ALK inhibitor crizotinib (Xalkori) initially gained accelerated approval from the FDA in August 2011 based on an improvement in ORR for patients with ALK-positive NSCLC. In November 2013, crizotinib was granted a full regulatory approval based on an improvement in PFS and ORR when compared with chemotherapy in a phase III study. However, despite the benefits seen with this drug, many patients progress, warranting the investigation of second-generation agents.

Ceritinib

The lead agent in the race for a second-generation ALK inhibitor, ceritinib (Zykadia) entered clinical trials approximately at the same time that crizotinib gained initial approval. After less than four years of clinical research, ceritinib was granted an accelerated approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC following treatment with crizotinib.

The approval for ceritinib was based on 163 patients in a single-arm clinical trial demonstrating an ORR of 54.6% with a 7.4-month median DOR, according to investigator-assessed criteria. By blinded review, the ORR was 44% and the DOR was 7.1 months. Based on interim findings, the FDA granted ceritinib a Breakthrough Therapy designation, Priority Review, and Orphan Product designation.⁵

“The ability to deliver this drug for patients who have failed crizotinib or who have progressed on crizotinib remains very exciting for us,” Levy noted. “I’m very excited about this drug, and we’ll be participating in a clinical trial at our institution with this drug.”

AP26113 and Alectinib

Other next-generation ALK inhibitors are also being explored, including AP26113 and alectinib. In data presented at the 2013 European Cancer Congress (ECC) last September, AP26113 demonstrated an objective response in 22 (65%) of 34 patients with ALK-positive NSCLC. Additionally, 80% of patients with brain metastases had evidence of radiographic improvement.⁶

Adding to the collection of positive data, the second- generation ALK inhibitor alectinib demonstrated tumor regression in 43 of 46 patients (93.5%) in crizotinib-naïve patients with NSCLC, according to a Japanese study submitted for regulatory approval.⁷ The FDA granted alectinib a Breakthrough Therapy designation in September 2013,⁸ which coincided with the presentation of updated data from a phase I study at ECC. In this study, following progression on crizotinib, the ORR with alectinib was 59%.⁹

“Let’s remember that crizotinib started its life as a MET inhibitor, and the observation was that it worked in an ALK-translocated patient. So it got off the ALK exit and got approved,” Socinski said. “I think for people who know a lot more about drug development than I do, no one ever felt crizotinib was the most potent ALK inhibitor.”

Sequencing Treatments

With the onslaught of new therapies, the next question will focus on sequencing. Each treatment interacts differently, allowing some to be sequenced while others cannot. For example, crizotinib followed by ceritinib appears to be an effective sequence, while prior treatment with crizotinib or ceritinib was shown to increase toxicity in patients treated with AP26113, the panelists noted. Overall, future research will focus on this area, but these early findings set the groundwork for an optimal sequence.

“What we don’t know is can we sequence these drugs and get from diagnosis to three, four, five, 10 years into the future,” Wakelee said. “I think this is all speculation. These studies haven’t been done. It’s not going to be clear if they ever will be done in that way, but, obviously, from the patient perspective that’s what we want to be thinking about.”

Second-Generation EGFR Inhibitors

A number of next-generation EGFR inhibitors are in early-phase clinical studies for patients with NSCLC. These therapies are being examined primarily in patients with EGFR T790M resistance mutations. The two leading therapies in this space, AZD9291 and CO- 1686, have demonstrated response rates of approximately 60% for patients with T790M mutations.

“The ability to deliver a targeted drug to an actionable mutation is very exciting for us, but, unfortunately and inevitably, as we know, these patients progress,” Levy said. “I think the new paradigm is coming up with newer therapies that can target these resistance mechanisms, which are responsible for patients progressing.”

These next-generation therapies are highly selective for EGFR T790M mutations. As a result, the usual side effects seen with EGFR inhibitors, such as rash and diarrhea, are rare. These therapies are poised to be game-changers, since T790M mutations occur in approximately 60% of patients with EGFR mutations.

“These drugs were designed to kill cells that are now dependent on T790M. They also are extremely effective against single EGFR mutants,” Kris said. “What they don’t do is effectively inhibit wild-type. So the usual side effects we see of rash and diarrhea are really pretty rare.”

Maintenance Strategies Explored

Multiple clinical trials have explored maintenance strategies using a variety of therapies for patients with NSCLC. Continuation maintenance approaches using first-line treatments beyond progression are commonly utilized for patients with NSCLC. Switch maintenance— changing to a new therapy—has been explored in several phase III studies.

In the SATURN study, erlotinib (Tarceva) was compared with placebo following four cycles of first-line platinum-based chemotherapy. The median OS with erlotinib was 12.0 months versus 11.0 months with placebo (HR = 0.81; P = .0088). The median PFS was 2.8 months with erlotinib versus 2.6 months with placebo (HR = 0.71; P <.0001).¹⁰

In the JMEN study, pemetrexed (Alimta) was compared with placebo following four cycles of platinum-based chemotherapy. The median OS was 13.4 months versus 10.6 months (HR = 0.79; P = .012) and the median PFS was 4.3 months versus 2.6 months (HR = 0.50; P < .0001), for pemetrexed and placebo, respectively.¹¹

These studies were conducted without the consideration of bevacizumab (Avastin), raising the question of whether this agent would add to the efficacy. To address this, the phase III ATLAS trial added bevacizumab to erlotinib following first-line treatment with chemotherapy plus bevacizumab. This study showed a significant increase in PFS but not OS.¹²

Following the success of switch maintenance therapy with pemetrexed in the JMEN trial, the PARAMOUNT study explored the drug beyond progression on four cycles of pemetrexed plus cisplatin. In this study, the median OS was 13.9 months versus 11.0 months (HR = 0.78, P = .0195)¹³ and the median PFS was 4.1 months versus 2.8 months (HR = 0.62; P < .0001), for pemetrexed and placebo, respectively.¹⁴

“Pemetrexed has now had two studies, the JMEN and the PARAMOUNT. Based on those studies, I do offer maintenance pemetrexed,” Levy said. “My go-to regimen is generally four cycles of carboplatin/ pemetrexed. And if they’ve achieved at least stable disease and they’re tolerating therapy, I will offer them single-agent maintenance pemetrexed.”

The next wave of trials sought to combine bevacizumab with pemetrexed in the PointBreak and AVAPERL studies. In the PointBreak trial, patients received firstline pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus first-line paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab. Overall, this study failed to significantly extend OS.¹⁵ “[PointBreak] was a completely negative trial.

The endpoint was overall survival. It did not show a difference. They did not show a difference in overall response rates,” Socinski said. “In my opinion, it showed a modest statistically significant benefit. I’m not overwhelmed by the clinical significance of the PFS benefit that was seen.”

In the AVAPERL study, patients received first-line bevacizumab, cisplatin, and pemetrexed for four cycles followed by maintenance bevacizumab alone or in combination with pemetrexed.

The median PFS was 7.4 months with the combination versus 3.7 months for single-agent bevacizumab (HR = 0.48; P < .001), with OS data still pending.¹⁶

A new study, ECOG5508, plans to build on evidence from previous studies, such as the JMEN trial. This study will compare maintenance therapy with bevacizumab and pemetrexed alone or in combination following four cycles of carboplatin/paclitaxel/bevacizumab for patients with NSCLC. The study hopes to enroll 1282 patients. This study will provide the first head-to-head comparison of various maintenance strategies for NSCLC.

“To me, [maintenance therapy] is the biggest nobrainer in oncology,” Kris said. “It’s a small number of patients. You say it works. You say it’s safe. The patient says, ‘Doc, this makes sense to me. My life is good because of this regimen. I would never stop it.’ But you ask that question every visit, and if it’s ‘Doc, I can’t use my keyboard,’ you’re done.”

References

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2. Garon EB, Balmanoukian A, Hamid O, et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). Presented at: the 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract MO18.02.
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7. New drug application filed for ALK inhibitor “alectinib hydrochloride” for the treatment of ALK fusion gene positive unresectable, recurrent/ advanced non-small cell lung cancer [news release]. Tokyo, Japan: Chugai Pharmaceuticals; October 8, 2013. http://www.chugai-pharm.co.jp/hc/ ss/english/news/detail/20131008113000.html. Accessed May 7, 2014.
8. Roche to share important oncology data at European Cancer Congress (ECC) [news release]. Basel, Switzerland: Roche; September 23, 2013. http://www.roche.com/media/media_releases/med-cor- 2013-09-23.htm. Accessed May 7, 2014.
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