New Data Establish Long-Term Efficacy for 2 Modern Modalities in NSCLC and Melanoma

Patrick Ott, MD, PhD

For nearly a decade, immunotherapy and molecularly targeted agents have been the focus of intense development. Now emerging evidence suggests that both modalities can deliver long-term benefits for patients, but the findings may prompt additional questions of how best to fit these transformative therapies into treatment landscapes.

Follow-up data from clinical trials in melanoma and non—small cell lung cancer (NSCLC)—2 tumor types in which immune checkpoint inhibitors have been widely adopted—show that subsets of patients survive for 5 or 10 years, or sometimes even longer (Table^1-6). The latest results are not changing standard treatment practices but suggest research directions toward methods that could extend survival further or provide cures, such as modified sequencing or triplet therapies.

The checkpoint immunotherapy era was launched in 2011 with the approval of ipilimumab (Yervoy), a CTLA-4 inhibitor, for the treatment of metastatic melanoma. Monoclonal antibodies directed at the PD-1/PD-L1 pathway have since become the dominant immunotherapy in melanoma, NSCLC, and nearly a dozen other cancer types, depending on the drug and indication.

Meanwhile, molecularly targeted therapies have advanced rapidly in both malignancies for patients with relevant mutations. In melanoma, 3 targeted therapy duos are approved in first-line settings for patients with metastatic or unresectable melanoma harboring BRAF V600 activating mutations.⁷ In NSCLC, sequencing studies have identified “pies within pies” of mutations, resulting in therapies directed at 5 abnormalities.⁸

Although immunotherapy has been hailed for its potential to deliver long-term results, recently reported trial results demonstrate that durability also can be achieved through molecularly targeted agents.

In melanoma, the National Comprehensive Cancer Network (NCCN) lists both modalities among the preferred first-line treatments for patients with metastatic or unresectable disease.

Category 1 options consist of anti— PD-1 monotherapy with either nivolumab (Opdivo) or pembrolizumab (Keytruda), combination immunotherapy with nivolumab and ipilimumab in certain circumstances, and 3 targeted therapy duos for patients with BRAF V600 mutation: dabrafenib (Tafinlar) plus trametinib (Mekinist), vemurafenib (Zelboraf) plus cobimetinib (Cotellic), and encorafenib (Braftovi) plus binimetinib (Mektovi). Combination targeted therapies are recommended for patients with the mutation who need an early response.⁷

In NSCLC, the NCCN recommends matching targeted therapies in the first line for patients with advanced or metastatic disease who test positive for mutations in EGFR or BRAF V600, rearrangement in ALK or ROS1, or an NTRK gene fusion.

For patients in that setting without mutations and PD-L1 expression ≥1%, first-line options are pembrolizumab as monotherapy or combined with chemotherapy and the PD-L1 inhibitor atezolizumab (Tecentriq) combined with chemotherapy and bevacizumab (Avastin) for patients with nonsquamous disease.⁸

Melanoma Findings

In advanced melanoma, immunotherapy is generally given first, although the issue is “hotly debated,” said Patrick Ott, MD, PhD, clinical director of the Center for Immuno- Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

Findings from a pooled analysis of the COMBI-d and COMBI-v trials demonstrated that one-third of patients with previously untreated unresectable or metastatic BRAF V600-mutant melanoma remained alive at 5 years following treatment with dual targeted therapy consisting of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib.¹

The median overall survival (OS) was 25.9 months (95% CI, 22.6-31.5). Of the 563 patients treated during the trials, 37% were alive at 4 years (95% CI, 33%-42%) and 34% (95% CI, 30%-38%) at 5 years. In terms of progression-free survival (PFS), the median was 11.1 months (95% CI, 9.5-12.8). PFS rates were 21% (95% CI, 17%-24%) at 4 years and 19% (95% CI, 15%-22%) at 5 years.¹

Moreover, the OS rate was 71% among those who achieved a complete response (CR; n = 109).¹ The objective response rate (ORR) in the pooled population was 68% (95% CI, 64%-72%). The CR rate was 19%, with a median duration of 36.7 months (95% CI, 24.1—not reached [NR]).

The results were the most mature data for a targeted therapy in advanced melanoma and confirm the long-term efficacy of tyrosine kinase inhibitors (TKIs) for many patients with BRAF mutations, Ott said.

However, in the frontline setting, immunotherapy may be preferred, particularly in light of the updated CheckMate 067 results reported last year.²

A total of 945 patients with previously untreated, unresectable, stage III or IV melanoma, known BRAF V600 mutation status, and an ECOG performance status of 0 or 1 were randomly assigned to nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg for 4 doses followed by nivolumab at 3 mg/kg; nivolumab at 3 mg/kg plus placebo; or ipilimumab at 3 mg/kg plus placebo.

The 4-year OS was 53% (95% CI, 47%-58%) in the combination group, 46% (95% CI, 41%-52%) in the nivolumab group, and 30% (95% CI, 25%-35%) in the ipilimumab group.²

Table. Long-Term Efficacy Results of Immunotherapy and Targeted Therapies in Melanoma and NSCLC^1-6 (Click to Enlarge)

At a minimum follow-up of 48 months, median OS was NR (95% CI, 38.2-NR) in the nivolumab plus ipilimumab group, 36.9 months (28.3-NR) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group.

Notably, 4-year OS was higher for patients with BRAF-mutated tumors than it was for those with wild-type BRAF: 62% versus 49%, respectively, in the combination arm; 50% versus 45% in the nivolumab group; and 33% versus 28% in the ipilimumab arm.²

In terms of responses, the ORRs were 58% in the combination arm, 45% for nivolumab monotherapy, and 19% for ipilimumab therapy. The median duration of response (DOR) was 50.1 months (95% CI, 44.0-NR) in the combination arm, NR in the nivolumab group (95% CI, 45.7-NR), and 14.4 months (95% CI, 8.3-NR) with ipilimumab monotherapy.

No trial data comparing the immunotherapy combination with dabrafenib—trametinib have been reported, but the nivolumab– ipilimumab results “support our thinking,” according to Ott. “I’m certainly in that camp—that immunotherapy should probably be done first,” he said.

“If you fail on BRAF inhibition, you may not actually have enough time to get the full benefit of immunotherapy. The thinking here is to start the treatment that has a higher chance of having a durable response. You have a lower response rate compared to the targeted therapy, but once you receive a response, there’s going to be a higher chance that it will maintain that response. If immune therapy loses that response, you can always give the targeted therapy, and that will invariably work because it works very fast and very reliably,” he said.

Jeffrey S. Weber, MD, PhD, deputy director at NYU Langone Health’s Perlmutter Cancer Center in New York, New York, said timing issues can also favor starting with immunotherapy. The process of obtaining genomic testing results to confirm BRAF mutation status and then ordering TKIs can take up to 2 weeks, whereas patients can be scheduled for immunotherapy infusion the next day and may prefer not to wait, he said.

In an effort to compare first-line approaches, ECOG launched a trial in 2014 to evaluate dabrafenib plus trametinib followed by ipilimumab and nivolumab versus ipilimumab plus nivolumab followed by dabrafenib and trametinib for patients with stage III or IV BRAF V600 melanoma. The phase III study, which aims to enroll 300 participants, is still recruiting.8 Weber said patients may be reluctant to participate, and completing accrual will take several years.

“It is a legitimate randomized trial to test a very important question. The problem is, the patients see the data you saw, and they say, ‘Why would I want to go on targeted therapy first? The results weren’t as good,’ ” Weber said.

NSCLC Results

In NSCLC, recent findings also have demonstrated long-term efficacy for the PD-1 inhibitors pembrolizumab and nivolumab, both introduced in second-line settings in 2015 as the first checkpoint immunotherapies available for the malignancy.^10,11

In the single-arm phase IB KEYNOTE-001 trial, the OS rate at 5 years among patients with NSCLC who received pembrolizumab was 23.2% for treatment-naïve patients (n = 101) and 15.5% for previously treated patients (n = 449), according to data presented at the 2019 American Society of Clinical Oncology Annual Meeting and published in the Journal of Clinical Oncology.³ Most patients in the treatment- naïve group (all but 11) did not have EGFR mutations or ALK translocations.

The median OS was 22.3 months (95% CI, 17.1-32.3) in treatment-naïve patients and 10.5 months (95% CI, 8.6-13.2) in previously treated patients. The investigator- assessed overall response rate was 41.6% in treatment-naïve patients and 22.9% in previously treated patients. The median DOR was 16.8 months for untreated patients and 38.9 months in those who received prior treatment.³

“The clinical implications [of the KEYNOTE-001 trial] are that advanced NSCLC is not exactly what it has traditionally been,” lead study author Edward B. Garon, MD, MS, said in interview with OncologyLive^® “Although it is a situation where there are many patients who don’t derive much benefit from therapy, now there is a sizable group of patients who experience the promise of immunotherapy with long, durable responses leading often fairly normal lives even many years after their diagnoses.

“It’s not as surprising from where we sit today, having seen the development over the last several years, but it is surprising when one takes into account where the field was when we first started this study in 2012,” added Garon, an associate professor at the David Geffen School of Medicine at the University of California, Los Angeles. “We were able to show that we had a significant 5-year OS rate among patients with advanced NSCLC. Prior to the publication, we would have anticipated a 5-year OS rate for advanced NSCLC somewhere around the 5% range. The study found that over 15% of patients were alive at 5 years.”

Corey J. Langer, MD, director of thoracic oncology at the Hospital of the University of Pennsylvania Abramson Cancer Center in Philadelphia, noted that in participants in KEYNOTE-001 with a PD-L1 tumor proportion score of 50% or greater, 5-year OS was 29.6% and 25% in treatment-naïve and previously treated patients, respectively.³

“The survival curves were starting to plateau. The suggestion, at least, was that not only were these durable responses but they [also] might be long-lasting. I hesitate to use the C-word, for cure, but we’ve seen similar things on a higher level in melanoma, and there’s no reason in the world that lung or other solid tumors might not follow suit, although clearly not to the extent we’ve seen in melanoma,” Langer said. He described survival of 5 or more years as the de facto equivalent of a cure.

Similarly, long-term findings confirm the benefits of nivolumab therapy in patients with previously treated NSCLC, according to a pooled analysis of data from the phase III CheckMate 017 and CheckMate 057 trials presented at the 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC 2019).⁴

In both studies, patients who experienced disease progression during or after first-line platinum-based chemotherapy were randomized 1:1 to receive nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until progression or unacceptable toxicity. After completing the primary analysis, patients in the docetaxel arm who were no longer experiencing benefit from the treatment were permitted to cross over to receive nivolumab.

Nivolumab therapy was associated with a 5-year OS rate of 13.4% compared with 2.6% with docetaxel. The OS benefit with nivolumab was observed across all patient subgroups, including those with PD-L1 expression on <1% of tumor cells.

Results showed that among the patients who achieved an objective response to nivolumab, 32.2% continued to have a response at 5 years compared with 0% of patients who received treatment with docetaxel. The median DOR was 19.9 months and 5.6 months for the nivolumab and docetaxel arms, respectively. The 5-year PFS rates were 8.0% with nivolumab compared with 0% for those who received docetaxel.

“CheckMate 017 and 057 are the first phase III trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 5-fold increase in 5-year OS rates with nivolumab compared with docetaxel,” Scott Gettinger, MD, professor of internal medicine (medical oncology) at Yale Cancer Center in New Haven, Connecticut, who presented the findings at WCLC 2019, said in a press release. “Nivolumab remained well tolerated with no new safety signals.”¹²

Meanwhile, long-lasting responses have been recorded for patients with advanced NSCLC with genetic alterations who are treated with targeted therapies, with some populations experiencing particularly lengthy OS.

In one group of patients (n = 79) treated with gefitinib (Iressa), an EGFR TKI, the median duration of therapy was 11.1 years (range, 6.5-15.1). The 10-year and 15-year OS rates were 86% and 59%, respectively, from the initiation of therapy.¹³

Forty-eight patients (61%) experienced adverse events (AEs), and 21 patients (27%) had serious AEs. Gefitinib-related AEs were observed in 16 patients (20%), and 1 patient (1%) had a gefitinib-related serious AE. The gefitinib-related AEs were mostly gastrointestinal symptoms with diarrhea (7 patients; 9%), and 1 patient (1%) had a grade ≥3 reaction. Skin rash occurred in 5 patients (6%), and no patients had grade ≥3 rash.¹³

Langer described these patients as a “highly select” group. Gefinitib was approved in 2003, lost approval for new patients 2 years later, and was withdrawn from the US market in 2011. A total of 191 patients who were benefiting from gefitinib continued to receive the drug under the IRESSA Clinical Access Program (ICAP). The FDA later approved gefinitib for first-line treatment of patients with metastatic NSCLC and EGFR mutations.¹³

The investigators acknowledge that the ICAP study is limited by selection bias. They say the published literature suggests the median DOR to gefinitib is about 10 months, with just a subset of patients on the “tail of the curve” having durable responses lasting for years.

However, Langer noted that other TKIs also demonstrate relatively lengthy responses in advanced NSCLC. In a pooled analysis of 2 phase II studies of patients with centrally confirmed, EGFR T790M mutation—positive disease, treatment with osimertinib (Tagrisso) resulted in a 36-month OS rate of 37%. Median OS was 26.8 months (95% CI, 24.0-29.1), and the 12- and 24-month OS rates were 80% and 55%, respectively.⁶

Another long-term analysis retrospectively reviewed 110 patients with ALK-positive NSCLC.⁵ A total of 105 patients received crizotinib (Xalkori) as their initial ALK inhibitor. With a median follow-up time of 47 months, the median OS from diagnosis of stage IV disease was 81 months (6.8 years). The 4- and 5-year survival rates were 73% and 60%, respectively.⁵

For ALK-positive patients, “I would say my clinical practice pretty much coheres with that observation,” Langer said. “I have a bunch of patients out now 4, 5, 6, 7 years.”

Other ALK-targeting drugs may be shown to provide even longer responses as trials mature. Interim results from the phase III ALEX trial show that median PFS was 34.8 months with alectinib (Alecensa) versus 10.9 months with crizotinib.¹⁴

Although the ALK and gefitinib studies were conducted in select patient populations, “the fact that we can achieve those long-term results in specific groups is an extremely significant progression of therapy for patients with advanced non—small cell lung cancer,” Fred R. Hirsch, MD, PhD, lead author of the gefitinib study, said in an interview.

In the gefitinib study, “the safety data are very good even with long-term treatment with those TKIs,” said Hirsch, who is executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute at Mount Sinai in New York, New York.

As more results are published on treatment of advanced NSCLC, the data have confirmed the practice of giving targeted therapies first if indicated and immunotherapy in later lines, Langer said. “The preponderance of data in the last year really pointed to that sequence. If anything, [they’ve] only reinforced it,” he said.

Langer noted that enrollment in a phase II trial of pembrolizumab in TKI-naïve patients with EGFR mutation—positive, advanced NSCLC and PD-L1–positive (≥1%, 22C3 antibody) tumors was halted early because of lack of efficacy and resulted in 2 deaths within 6 months of enrollment.¹⁵

Another study found that 15% (6 of 41; 95% CI, 7%-29%) of patients treated with sequential PD-L1 blockade followed by osimertinib developed severe immunerelated AEs (irAEs).¹⁶ Twenty-four percent of patients who began osimertinib within 3 months of prior PD-L1 blockade (5 of 21; 95% CI, 10%-45%) experienced severe irAEs compared with 13% who began within >3 to 12 months (1 of 8; 95% CI, 0%-50%).

No severe irAEs were identified among patients who began osimertinib at >12 months (95% CI, 0%-28%) or among those who were treated with osimertinib followed by sequential PD-L1 blockade (95% CI, 0%-14%) or treated by PD-L1 blockade followed by other EGFR TKIs (afatinib or erlotinib; 95% CI, 0%-15%).¹⁶

Nonetheless, Langer said he often sees patients with NSCLC who were treated with immunotherapy while they waited for their genomic test results to arrive. “It would be nice if there were some justification for doing it, but sadly, there’s none whatsoever,” Langer said. “If you do it in the wrong sequence, you compromise the outcomes and you heighten toxicity.”

Langer said he’s looking forward to seeing trial results that give more nuanced perspectives on acquired resistance in TKIs and point to ways to extend survival further for patients on targeted therapies. These include trials that combine chemotherapy with TKIs.

One such study of gefitinib, carboplatin, and pemetrexed found the combination had same PFS2—defined as a comparison of progressive disease in the reference arm and the experimental arm&mdash;as gefitinib alone but much longer OS of 52.2 months versus 38.8 months (HR, 0.695; P = .013).¹⁷ “They’re getting better outcomes, not so much higher response rates but longer survival. What was done with gefitinib and erlotinib, we need to do...now with osimertinib,” Langer said.

Hirsch noted that there are many outstanding questions about sequencing therapies. “Currently, the paradigm is, if you have a molecular driver, this patient should have a molecularly targeted [agent] upfront. I think we all agree upon that,” he said. “What will happen if or when the patient progresses after specific targeted therapies? I think that remains to be established.”

“This is the first time we have these longterm data with these new drugs. Having a 50% overall survival in metastatic melanoma patients is remarkable. That would have been impossible before we had these therapies. It’s really related to the efficacy of these drugs,” Ott said.

References

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