Doctors Debate: Is Single-Agent Immunotherapy or Combination Immunotherapy Best for First-Line Treatment of Advanced NSCLC?

Paul A. Bunn, Jr, MD

In the frontline setting of advanced non–small cell lung cancer (NSCLC), multiple immunotherapy agents have demonstrated the ability to improve survival in patients with metastatic disease when used alone for those with high PD-L1 expression and when combined with chemotherapy for those with PD-L1 expression of 0% to 49%. The presence of primary and acquired resistance to the FDA-approved immune checkpoint inhibitors, however, has led to discussions among medical oncologists who have tried both the single-agent and combination strategies for the treatment of this patient group.

Karen L. Reckamp, MD, MS

During a Medical Crossfire® at the 21st Annual International Lung Cancer Congress®, hosted by Physicians Education Resource®, LLC (PER®), Paul A. Bunn, Jr, MD, distinguished professor of medicine-medical oncology at the University of Colorado School of Medicine in Aurora, debated with Karen L. Reckamp, MD, MS, director of medical oncology and associate director of clinical research at Cedars Sinai in Los Angeles, California, about frontline single-agent immune checkpoint inhibitors versus combined chemotherapy and immunotherapy for the treatment of patients with advanced NSCLC.^1,2

Single-Agent Immunotherapy is Best for Frontline Advanced NSCLC

During the first debate presentation, Bunn argued that single-agent immunotherapy was sufficient to treat patients with metastatic NSCLC with high PD-L1 expression (>49%), a claim he supported based on the results from 2 large randomized clinical trials.¹

“I concede that patients with a total proportion score [TPS] of 0% to 49%, chemotherapy plus immunotherapy would probably be better unless the patients could not tolerate the chemotherapy,” he said.

Research Supporting First-line Use of Single-Agent Immunotherapy in Advanced NSCLC

Bunn turned to the results of phase 3 trials including KEYNOTE-024 (NCT02142738), KEYNOTE-042 (NCT02220894), and IMpower110 (NCT02409342)—which examined combinations of either pembrolizumab or atezolizumab versus platinum doublet chemotherapy—to show the benefit of single-agent immunotherapy in terms of progression-free survival (PFS), overall survival (OS), and response rate.

In the KEYNOTE-024 study, 305 previously untreated patients were randomized 1:1 to receive either fixed-dose pembrolizumab 200 mg every 3 weeks or physician’s choice of platinum chemotherapy doublets for 4 to 6 cycles. Patients in the chemotherapy arm had the option to cross over to pembrolizumab if the safety criteria were met.^1,3

Ultimately, the study was positive for the primary end point of PFS superiority after pembrolizumab demonstrated a 10.3-month median PFS compared with 6.0 months in the chemotherapy doublet arm (HR, 0.50; 95% CI, 037-0.68; P < .001) in the intention-to-treat population. It was estimated that 62.1% of patients who received pembrolizumab were alive and progression free at 6 months versus 50.3% of those who received the chemotherapy regimen. The PFS benefit was also seen in all the subgroups evaluated in the study. According to the 5-year OS update presented at the European Society for Medical Oncology Virtual Congress 2020, the median OS was 26.3 months in the pembrolizumab arm compared with 13.4 months in the chemotherapy arm (HR, 062; 95% CI, 0.48-0.81).⁴

A higher objective response rate (ORR) of 44.9% was observed with pembrolizumab compared with chemotherapy, which led to an ORR of only 27.8%. The median duration of response was not reached with pembrolizumab versus 6.3 months with chemotherapy.

KEYNOTE-042, another randomized, open-label phase 3 trial of pembrolizumab versus platinum-based chemotherapy, included a cohort of patients with a TPS of 1% to 49%. A total of 1275 patients were randomized 1:1 to receive pembrolizumab or investigator’s choice of platinum-based chemotherapy, similar to the dosing and schedule from KEYNOTE-024.^1,5

Pembrolizumab monotherapy led to significantly longer OS compared with chemotherapy. Notably, among the subgroup of patients in the study who had a TPS of at least 50%, the median OS was higher at 20.0 months in the pembrolizumab arm versus 12.2 months in the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0003), suggesting that single-agent immunotherapy may be the best approach for treatment of this patient population, Bunn explained.

Similarly, in the IMpower110 trial, single-agent atezolizumab (Tecentriq) resulted in a significant improvement in median OS versus chemotherapy in patients with PD-L1 expression at least 1% (HR, 0.59; 95% CI, 0.40-0.89; P = .01).⁶

Bunn said these study results taken together prove a survival benefit with single-agent immunotherapy, which is consistent in patients with a TPS of at least 50%. But even although these data back Bunn’s argument, he explained that his stance did not hold completely true for patients with a TPS of 1% to 49%.

“There is limited evidence that patients with a TPS of 2% should not receive chemotherapy, but they might tolerate immunotherapy adequately. There are also patients that have a TPS of 0%, meaning none of the cells are expressing PD-L1. The standard treatment for these [patients] is chemotherapy plus single-agent immunotherapy,” Bunn said.

Possibilities for Combination Immunotherapy

Recent research has shown new possibilities for combination immunotherapy that may offer deeper responses to treatment. One such study is CITYSCAPE, a clinical trial of tiragolumab plus atezolizumab (Tecentriq) compared with placebo plus atezolizumab as frontline treatment of patients with stage IV NSCLC with EGFR/ALK wild-type disease and a PD-L1 TPS of at least 1% (NCT03563716).^1,7

In 135 patients, the ORR was 31% with the immunotherapy combination compared with 16% in the control arm. Significantly, the ORR in the group with a PD-L1 TPS of at least 50% was superior to that of the group with a PD-L1 TPS of 1% to 49%. Corresponding response rates with tiragolumab/atezolizumab were 66% and 16% versus 24% and 18% with the control.

Bunn stated that these data show potential for combination immunotherapy in the future but that single-agent immunotherapy is better at present.

Summing up his presentation, Bunn told Targeted Therapies in Oncology (TTO) that single-agent pembrolizumab is better for the overall population of patients with advanced NSCLC, but that those with a low TPS of less than 49% may do better on pembrolizumab plus chemotherapy. On the other hand, those with a low TPS may actually benefit from combination immunotherapy, considering the lower responses and survival observed in these patients on single-agent immunotherapy.

Combination Therapy is Best for Frontline Advanced NSCLC

Reckamp argued that combination therapy is the most sensible treatment strategy for the frontline treatment of patients with advanced NSCLC. Her reasoning was that unlike monotherapy, combination therapy has the potential to alter tumor antigen presentation and antitumor responses, decrease immunosuppressive T-regulatory cells and myeloid-derived suppressor cells, activate T and B cells, address tumor heterogeneity, improve response rates in patients with systemic progression, and overcome mechanisms of primary and acquired resistance.²

“For the majority of patients with advanced NSCLC, most will need combination therapy in order to achieve maximum benefit from immune checkpoint inhibitor therapy,” Reckamp said in an interview with TTO. “For the patients who have greater than 50% PD-L1 [expression], there’s about a 40% response rate. [This shows] that many patients will not have tumor response with single-agent therapy.”

Reckamp said the pitfalls of single-agent immunotherapy and the advantages of combination are made clear through countless clinical trials, which she highlighted during her presentation. All the studies mentioned were of the FDA-approved PD-1/PD-L1 inhibitors pembrolizumab, atezolizumab, and nivolumab as well as the CTLA-4 inhibitor, ipilimumab.

The KEYNOTE Lung Cancer Trials

In the single-agent realm, KEYNOTE-042 was interpreted by Reckamp as a positive study of pembrolizumab in the overall population and in the subgroup of patients with high PD-L1 expression. However, the OS in patients with low PD-L1 expression (1%-49%) was unsatisfactory, with an HR of 0.92 (95% CI, 0.77-1.11). Overall, the limited benefits in patients with low PD-L1 expression relates to the challenge of resistance to immune checkpoint blockade. Such resistance can be resolved with combination treatment.⁸

In the phase 3 KEYNOTE-189 trial (NCT02578680), pembrolizumab in combination with chemotherapy significantly prolonged OS and PFS compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous NSCLC who did not harbor ALK or EGFR mutations.⁹

Patients were randomized 1:1 to fixed-dose pembrolizumab at 200 mg or placebo plus chemotherapy. In the intention-to-treat population, the median OS was not reached in the pembrolizumab arm versus 11.3 months in the placebo arm (HR, 0.49; 95% CI, 0.38-0.64;
P < .001). This OS benefit was observed across all subgroups explored in the study.

The pembrolizumab arm had a median PFS of 8.8 months compared with 4.9 months in the placebo arm (HR, 0.52; 95% CI, 0.43-0.64; P< .001). The estimated 12-month PFS was 34.1% for the pembrolizumab/chemotherapy arm versus 17.3% for the placebo/chemotherapy arm.

Tumor responses in these patients reached 47.6% in those who received pembrolizumab versus 18.9% among those who received placebo (P< .001). The disease control rate (DCR) was 84.6% with pembrolizumab versus 70.4% with placebo. Responses were also durable in the pembrolizumab arm compared with the placebo arm, with a median duration of response of 11.2 months with the pembrolizumab combination compared with 7.8 months with the placebo combination.

Clinical benefit with pembrolizumab combined with chemotherapy over chemotherapy alone was also observed in patients with previously untreated NSCLC who have a squamous histology, according to the results of the double-blind, randomized phase 3 KEYNOTE-407 trial (NCT02775435). The study showed that the addition of pembrolizumab to the chemotherapy combination of carboplatin plus paclitaxel or nab-paclitaxel (Abraxane) significantly improved both OS and PFS.¹⁰

Patients were randomized 1:1 to receive 200 mg of pembrolizumab or placebo plus chemotherapy. Treatment was continued until radiographic disease progression, unacceptable toxic effects, discontinuation by an investigator’s decision, or withdrawal of patient consent.

Pembrolizumab plus chemotherapy achieved a median OS of 15.9 months compared with 11.3 months in the placebo arm (HR, 0.64; 95% CI, 0.49-0.85; P < .001). The median PFS was 6.4 months in the pembrolizumab combination arm compared with 4.8 months in the placebo combination arm (HR, 0.56; 95% CI, 0.45-0.70; P < .001).

Combining the results from both KEYNOTE-407 and KEYNOTE-189, Reckamp noted that combination chemotherapy and immunotherapy was better compared with single-agent chemotherapy in patients across PD-L1 expression, including those with a TPS score of 1% to 49%, with an HR for death of 0.55 (95% CI, 0.34-0.90) in KEYNOTE-189 and 0.57 (95% CI, 0.36-0.90) in KEYNOTE-407 in this group.

Atezolizumab in Combination Regimens

In patients with chemotherapy-naive stage IV nonsquamous NSCLC, atezolizumab combined with chemotherapy demonstrated a significant and clinically meaningful improvement in OS and PFS compared with chemotherapy, according to results from the randomized, open-label phase 3 IMpower130 trial (NCT02367781).¹¹

In the wild-type intention-to-treat population of patients receiving either the combination of atezolizumab plus chemotherapy or chemotherapy alone (n = 679), the 12-month OS rates were 63.1% compared with 55.5%, respectively. At 24 months, atezolizumab plus chemotherapy had a 39.6% OS rate compared with 30% with chemotherapy alone. The median OS was 18.6 months with the atezolizumab combination compared with 13.9 months with chemotherapy alone (HR, 0.79; 95% CI, 0.64-0.98; P = .033).

The CheckMate Lung Cancer Trials

Although atezolizumab and pembrolizumab combination clinical trials demonstrated improvements in OS and PFS compared with chemotherapy across NSCLC subgroups, Reckamp said the combination immune checkpoint inhibition has been predominantly seen with nivolumab and ipilimumab.

In CheckMate 227 (NCT02477826), patients with at least 1% PD-L1 expression and those with less than 1% PD-L1 expression were stratified to assess the efficacy of the combination of nivolumab and ipilimumab. A total of 1189 patients with at least 1% PD-L1 expression were randomized 1:1:1 to receive nivolumab/ipilimumab, nivolumab monotherapy, or chemotherapy. In the cohort with less than 1% PD-L1 expression (n = 550), patients received nivolumab/ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone.¹²

In those with PD-L1 expression of 1% or greater, median OS favored the nivolumab/ipilimumab arm at 17.1 months versus 14.9 months with chemotherapy alone (HR, 0.79; 95% CI, 0.65-0.96; P = .007). Single-agent nivolumab was also compared with chemotherapy alone in this group, which showed that nivolumab had a 15.7-month median OS compared with 14.9 months with chemotherapy (HR, 0.88; 95% CI, 0.75-1.04), demonstrating no significant benefit with single-agent immunotherapy.¹³

Another trial, CheckMate 9LA (NCT03215706), showed that nivolumab/ipilimumab plus chemotherapy led to a statistically significant improvement in OS compared with chemotherapy alone. The median OS was 14.1 months in the immunotherapy combination arm compared with 10.7 months in the chemotherapy-only arm (HR, 0.69; 95% CI, 0.55-0.87; P= .0006), according to interim analysis data. The updated results presented during the American Society of Clinical Oncology 2020 Virtual Scientific Program were consistent with the interim analysis showing a 15.6-month median OS with nivolumab/ipilimumab plus chemotherapy compared with 10.9 months with chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80).

Overall, Reckamp said the CheckMate lung cancer trials further solidify her argument that combination therapies with immunotherapy improve outcomes in patients with advanced NSCLC. She also noted that the ability to achieve clinical benefit in patients with driver mutations was an unmet need in the single-agent immunotherapy realm that could potentially be addressed with combination immunotherapy.

“Generally, we talk about patients who don’t have driver mutations because most of the trials in the frontline setting with combination therapy did not include patients with driver mutations. The only place we have evidence for patients with driver mutations having benefit with immunotherapy is with combination therapy, and that was in the IMpower150 trial where a subset of patients had an EGFR mutation.”

Benefit for Patients with EGFR-positive NSCLC

In the open-label, randomized phase 3 IMpower150 trial (NCT02366143), atezolizumab was administered in the first-line setting to patients with metastatic nonsquamous NSCLC.^14,15

In the EGFR-mutated population, atezolizumab plus bevacizumab and chemotherapy reached a median PFS of 10.2 months compared with 6.9 months with bevacizumab plus chemotherapy only (HR, 0.61; 95% CI, 0.36-1.03).16 In comparison, Reckamp pointed out that patients with both EGFR and ALK alterations have never derived benefit from mono-immunotherapy. She also noted that like many of the monotherapy trials, patients with EGFR- and ALK-positive NSCLC were excluded from the trials and using combination immunotherapy and chemotherapy and recommended that further studies include these subgroups.

In conclusion, based on the clinical trials highlighted during her presentation, Reckamp stated that an integrated immunotherapy treatment not only benefits advanced NSCLC but is also superior to anti–PD-L1 monotherapy.

_References:

_{1. Bunn PA. Lung cancer single agent immunotherapy 2020. Presented at: 21st Annual International Lung Cancer Congress®, hosted by Physicians’ Education Resource®, LLC (PER®); July 23-25, 2020; Virtual.}

_{2. Reckamp KL. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. Presented at: 21st Annual International Lung Cancer Congress®, hosted by Physicians’ Education Resource®, LLC (PER®); July 23-25, 2020; Virtual.}

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_{7. Rodríguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503}

_{8. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥1%: open-label, phase 3 KEYNOTE-042 study.
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_{10. 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}

_{11. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7);924-937. doi:10.1016/S1470-2045(19)30167-6}

_{12. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231}

_{13. Peters S, Ramalingam S, Paz-Ares L, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) versus platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 part 1 final analysis. Ann Oncol. 2019;30(suppl 5):V913-V914. doi:10.1093/annonc/mdz394.075}

_{13. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501}

_{14. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948}

_{15. Reck M, Mok TSK, Nishio M, et al; IMpower150 Study Group. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7(5):387-401. doi:10.1016/S2213-2600(19)30084-0}