The Lingering Questions in Immunotherapy

March 19, 2020

Although accumulating data continue to show immunotherapy as a major step forward in the treatment of patients with non–small cell lung cancer (NSCLC), questions regarding optimal sequencing and treatment duration still remain. At the 17th Annual Winter Lung Cancer Conference®, hosted by Physicians’ Education Resource®, LLC, multiple presentations looked for answers to address these issues.

Although accumulating data continue to show immunotherapy as a major step forward in the treatment of patients with non–small cell lung cancer (NSCLC), questions regarding optimal sequencing and treatment duration still remain. At the 17th Annual Winter Lung Cancer Conference®, hosted by Physicians’ Education Resource®, LLC, presentations from Karen Kelly, MD and Gilberto de Lima Lopes, MD, looked for answers to address these issues.

Treatment Initiation

While the use of immune checkpoint inhibitors, as a monotherapy and in combination with chemotherapy, has demonstrated benefits for patients with NSCLC, the key to unlocking the full therapeutic potential for these treatments, said Kelly, an associate director for clinical research at the University of California Davis Comprehensive Cancer Center, lies in the timing of treatment initiation.1 “For a majority of our patients who do not have oncogenic-driven cancers, there is now overwhelming and compelling data for the role of immune checkpoint inhibitors, either with chemotherapy or as monotherapy in the first-line setting,” acknowledged Kelly.2

She noted 2 relevant trials that studied concurrent versus sequential immunotherapy-KEYNOTE-189 (NCT02578680), which examined platinum chemotherapy plus pemetrexed with or without pembrolizumab (Keytruda), and KEYNOTE-407 (NCT02775435), which looked at carboplatin plus paclitaxel or nab-paclitaxel (Abraxane) chemotherapy with or without pembrolizumab.3,4 Combination therapy with pembrolizumab showed superior outcomes over placebo in both trials, with an overall survival (OS) rate at 12 months of 69.2% vs 49.4% (hazard ratio (HR), 0.49; 95% CI, 0.38-0.64; P <.001) in KEYNOTE-189, and a median OS of 15.9 versus 11.3 months (HR for death, 0.64; 95% CI, 0.49-0.85; P <.001) in KEYNOTE-407.

Patients in the placebo arms of KEYNOTE-189 (n = 206) and KEYNOTE-407 (n = 281) crossed over to receive pembrolizumab after disease progression at rates of 41% and 32%, respectively.3,4 Survival data for those patients were inferior to that of those who received concurrent therapy, noted Kelly.

“We have learned a lot in…recent years about the association of chemotherapy with immunotherapy and the tumor microenvironment,” said Kelly during her presentation. “The dogma we held, that chemotherapy was 100% immunosuppressive, we now know is false. While [chemotherapy] can be immunosuppressive, it can also be immunostimulatory.”

A third trial, the currently enrolling phase III INSIGNIA study (NCT03793179), aims to specifically address the sequencing debate. INSIGNIA will randomize patients to 1 of 3 arms: (1) frontline pembrolizumab followed by chemotherapy in the second line; (2) frontline pembrolizumab followed by pembrolizumab plus chemotherapy in the second line; or (3) the control arm of induction therapy with combination chemotherapy and pembrolizumab with maintenance pembrolizumab and pemetrexed.5

Finding the Finish Line

For patients with metastatic NSCLC, disease progression and toxicity have been 2 of the commonly used benchmarks to determine cutoff targets for treatment with programmed cell death protein 1(PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors. However, the solution for handling those patients who tolerate treatment and do not experience progression is not that obvious, according to de Lima Lopes.6

de Lima Lopes, an associate professor of clinical medicine and associate director for global oncology at Sylvester Comprehensive Cancer Center, University of Miami Health System, noted that cumulative data from the randomized trials that have been conducted so far suggest that those patients who have been treated with PD-1/PD-L1 inhibitors for 1 year should continue treatment until disease progression, unacceptable toxicity, or the 2-year mark is reached. 

“What we have seen in the clinical trials is that we have either continued immunotherapy until disease progression or toxicity,” said de Lima Lopes. “In the case of [trials conducted with] pembrolizumab, we have stopped at 2 years.”

In the phase IIIb/IV CheckMate 153 trial (NCT02066636), which was the first randomized trial to evaluate the duration of a PD-1/PD-L1 therapy, nivolumab (Opdivo) as a monotherapy was administered every 2 weeks for up to 1 year or until disease progression.7 Patients who completed 1 year of therapy were then randomly assigned to continuous therapy or observation with the option to resume nivolumab at progression. A total of 220 patients remained on treatment at 1 year. Those who continued on nivolumab had an improvement in progression-free survival versus those who stopped therapy (not reached vs 10.3 months; HR, 0.42; 95% CI, 0.25-0.71).7,8

Eighty-seven patients in the discontinuation arm had a response or stable disease at the time of randomization. Forty-three (49%) patients had disease progression after discontinuation, with 34 of those patients (79%) subsequently retreated with nivolumab. The median duration between progression and retreatment was 0.6 months (range, 0.1-4.9) and the median duration of retreatment was 3.8 months (range, 0.1-17.5).8

“These [data] answer the question, at least for now, that 1 year [with nivolumab] is probably not enough,” de Lima Lopes said. “Would I stop at 1 year? Only if there is good reason.”

Long-term follow-up data from the KEYNOTE-10 trial (NCT01905657) showed that patients who completed 2 years of pembrolizumab had a durable response with manageable adverse events.9 “Importantly, among patients who stopped [treatment with pembrolizumab] and then progressed, 14 patients did get a second course of pembrolizumab and of those patients, 43% had a partial response and 36% had stable disease; so, we do salvage some patients if they have been on immunotherapy for 2 years.”

Ultimately, de Lima Lopes acknowledged that the decision to continue or discontinue treatment is made on an individual patient-by-patient basis. “Usually what happens is I will talk to a patient who is approaching 2 years [on immunotherapy] if they still have a continued response or stable disease,” de Lima Lopes said. “One patient may say, ‘You tell me what to do, doc.’ But typically, we have a short discussion with the data I have just shown you and about half of my patients elect to continue [therapy] and half want to stop.” 

 

 

References:

REFERENCES

1. Kelly K. When to start immunotherapy. Presented at: 17th Annual Winter Lung Cancer Conference, hosted by Physicians’ Education Resource®, LLC; February 7-9, 2020; Miami Beach, FL.

2. Lovely B. Optimal immunotherapy sequencing remains elusive in lung cancer. OncLive website. https://www.onclive.com/conference-coverage/winter-lung-2020/optimal-immunotherapy-sequencing-remains-elusive-in-lung-cancer?p=1. Published February 8, 2020. Accessed February 23, 2020.

3. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.

4. Paz-Ares L, Luft A, Vicente D, et al. KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi: 10.1056/NEJMoa1810865.

5. Firstline Pembrolizumab Alone or in Combination With Pemetrexed and Carboplatin in Induction/Maintenance or Postprogression in Treating Patients With Stage IV Non-squamous Non-small Cell Lung Cancer (INSIGNIA). Clinicaltrials.gov identifier: 03793179. https://clinicaltrials.gov/ct2/show/NCT0379179?term=03793179&draw=2&rank=1. Accessed February 24, 2020.

6. de Lima Lopes G. When to stop immunotherapy. Presented at: 17th Annual Winter Lung Cancer Conference; February 7-9, 2020; Miami Beach, FL.

7. Spigel DR, McCleod M, Hussein MA, et al. CheckMate153: randomized results of continuous vs 1-year fixed-duration nivolumab in patients with advanced non-small cell lung cancer. Presented at: European Society for Medical Oncology Congress 2017; September 8, 2017; Madrid, Spain.

8. Lovely B. Finding the immunotherapy finish line remains a challenge in NSCLC. OncLive website. https://www.onclive.com/conference-coverage/winter-lung-2020/finding-the-immunotherapy-finish-line-remains-a-challenge-in-nsclc. Published February 9, 2020. Accessed February 23,2020.

9. Herbst RS, Garon EB, Kim DW, et al. Long-term survival in patients  with advanced NSCLC in the KEYNOTE-010 study overall and in patients who completed 2 years of pembrolizumab. Presented at: European Society for Medical Oncology Congress 2018; September 19-23, 2018; Munich, Germany

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