Langer Highlights the Impact of Chemoimmunotherapy in NSCLC

Corey J. Langer, MD

There has been a major paradigm shift with the combination of immunotherapy and chemotherapy in non—small cell lung cancer (NSCLC), according to Corey J. Langer, MD.

Although impressive single-agent data have been seen with agents such as pembrolizumab (Keytruda) versus chemotherapy in a high—PD-L1 population, the combination of PD-L1 inhibitors and chemotherapy may prove to be beneficial in a broader group of patients.

KEYNOTE-021 cohort G was part of a large phase II study combining pembrolizumab with various chemotherapy combinations and targeted therapies—a trial that set the stage for this therapeutic approach and was the basis for the FDA approval of frontline pembrolizumab with carboplatin/pemetrexed in May 2017. The standard arm was pembrolizumab plus carboplatin for 4 cycles, with or without pembrolizumab, given at a fixed dose for up to 2 years with pemetrexed given as maintenance in the absence of toxicity or progression.

Updated findings from KEYNOTE-021 cohort G were presented at the 2018 ASCO Annual Meeting.¹ The overall response rate (ORR) with pembrolizumab plus carboplatin and pemetrexed was 56.7% versus 30.2% with carboplatin and pemetrexed (P = .0016). The addition of pembrolizumab to carboplatin and pemetrexed resulted in a greater progression-free survival (PFS; HR, 0.53; 95% CI, 0.33-0.86; P = .0049). The median PFS for pembrolizumab plus chemotherapy was 24.0 months (95% CI, 8.5-NR), compared with 9.3 months (95% CI, 6.2-14.9) for chemotherapy alone.

Median overall survival (OS) for the chemoimmunotherapy combination was not reached (95% CI, 24.5-NR) and was 21.1 months (95% CI, 14.9-NR) for carboplatin and pemetrexed alone.

“These are unprecedented findings,” said Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania. “Granted, this is a small, randomized, phase II trial that is in mostly academic centers, but this trial accrued ahead of schedule. We had no trouble findings patients for this effort.”

These results laid the framework for KEYNOTE-189, which Langer said is essentially the phase III version of the phase II trial. The eligibly criteria are identical, enrolling nonsquamous patients without common oncogenic drivers. However, Langer noted that there are some salient differences. This was a 2:1 randomization, there was a choice of carboplatin or cisplatin, and it was a placebo-controlled study. Crossover was built into this trial as it was in KEYNOTE-021 cohort G.

Data from KEYNOTE-189 presented at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine showed that combining pembrolizumab with standard chemotherapy in the frontline setting reduced the risk of death by more than 50% in patients with nonsquamous NSCLC without EGFR or ALK abnormalities.^2,3 The estimated 12-month OS rate was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1%-56.2%) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P <.001) at a median follow-up of 10.5 months.

The median PFS in the pembrolizumab group was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43 to 0.64; P <.001). Median OS was not reached in the pembrolizumab group, while it was 11.3 months (95% CI, 8.7-15.1) in the control arm.

“One very interesting observation that had not been heralded in the randomized phase II trial was renal toxicity,” Langer noted. “Instances of renal insufficiency were 5% in the pembrolizumab combination versus the control arm.”

Most of the adverse events (AEs) in all patients were grades 1/2, with nausea, anemia, and fatigue being the most common.

Langer said that these results pose the question of what to give patients with a PD-L1 expression ≥50%: singleagent pembrolizumab or the triplet? There is a rationale for pembrolizumab monotherapy, there is no head-to-head of the single-agent versus the doublet, and KEYNOTE-021 cohort G was a relatively small randomized phase II study, he noted. “Clearly, single-agent pembrolizumab has less toxicity, much lower cost, and is much more convenient, and it doesn’t preclude the option of going to pembrolizumab plus carboplatin with or without bevacizumab at the time of progression,” said Langer.

He argued, however, that the response rate from KEYNOTE- 021 cohort G was 80%, and over 60% in KEYNOTE-189, which compared favorably to single-agent pembrolizumab in the same setting. There were also very low rates of primary progression, and initial PFS is increasing over time in the phase II trial.

“The worst conversation that we have in clinic is the progression conversation; it stops the clinic cold. Not only does it contribute to a detrement in the patient and their family’s quality of life, it [also] decreases our quality of life—the doctors, nurses, and physician’s assistants that are taking care of them,” said Langer.

Langer said that his practical strategy for patients with a PD-L1 expression ≥50% is based on a handful of clinical factors. Pembrolizumab alone is for patients who are older or frailer, have a lower metastatic burden, have significant comorbidities, or have a borderline performance status. The triplet of pembrolizumab plus pemetrexed/carboplatin is more suited for patients who are younger, with a higher metastatic burden, more aggressive disease, or have limited comorbidities.

For patients with NSCLC who have oncogenic drivers such as ALK or EGFR abnormalities, immunotherapy is usually not recommended. However, bevacizumab (Avastin) could be a potential option, as it has known antiangiogenic effects and immunomodulatory effects in its inhibition of VEGF. The inhibition of VEGF can promote T-cell priming and activation via dendritic cell maturation and normalization of the tumor vasculature through VEGF inhibition increased T-cell tumor infiltration, Langer explained.

“VEGF blockade can establish an immune-permissive tumor microenvironment by decreasing myeloid-derived suppressor cell and regulatory T-cell populations,” continued Langer. “Ultimately, tumor cell killing by chemotherapy may expose the immune system to high levels of cancer cell antigens.”

IMpower150 is a large randomized phase III study of patients with stage IV or recurrent metastatic nonsquamous NSCLC who are chemotherapy-naïve. The study has 3 arms: bevacizumab, carboplatin, and paclitaxel (BCP); atezolizumab (Tecentriq) plus bevacizumab, carboplatin, and paclitaxel (ABCP); and atezolizumab plus carboplatin and paclitaxel (ACP). The co-primary endpoints were PFS in the intent-to-treat (ITT) population, as well as in the gene signature population, T-effector gene signature—high. Patients with EGFR/ALK rearrangements in this trial must have progressed on prior therapy with TKIs.

Survival was significantly improved by adding atezolizumab to carboplatin, paclitaxel, and bevacizumab, with a median PFS of 8.3 months compared with 6.8 months with BCP (HR, 0.59; 95% CI, 0.50-0.70; P <.0001).^4,5 The median OS was 19.2 months (95% CI, 17.0-23.8) compared with 14.7 months (95% CI, 13.3-16.9) in the BCP arm (HR, 0.78; 95% CI, 0.64-0.96; P = .0164). Additionally, the 24-month OS rate with atezolizumab was 43% versus 34% for BCP.

Langer said that these results suggest additivity, if not synergy, for the combination of an angiogenesis inhibitor and a PD-L1 inhibitor. The 2 groups that seemed to benefit the most were patients with liver metastases and those who had EGFR or ALK rearrangements. There was also a survival benefit for those with high PD-L1 expression, Langer added.

Specifically, there was a 46% reduction in the risk of death with ABCP versus BCP for those with liver metastases (HR, 0.54; 95% CI, 0.33-0.88) and a 46% reduction in the risk of death for patients with EGFR/ALK-mutated NSCLC (HR, 0.54; 95% CI, 0.29-1.03).

The most common grade 3/4 immune-related AEs were rash (4% with ACP, 2% with ABCP, and 1% with BCP) and hepatitis (3%, 5%, and 1%, respectively). Langer said these were anticipated.

“Does this affect the current treatment paradigm? It is an attractive option in TKI-refractory patients with molecular aberrations, but I’d love to see a phase II or phase III trial that looks at pemetrexed in this setting,” Langer said.

In squamous NSCLC, results from the phase III IMpower131 study presented at the 2018 ASCO Annual Meeting showed that the addition of atezolizumab to frontline carboplatin and nab-paclitaxel (Abraxane) delayed the risk of progression or death by 29% compared with chemotherapy alone for patients with advanced disease.⁶

The median PFS at a median follow-up of 17.1 months was 6.3 months (95% CI, 5.7-7.1) with the addition of atezolizumab versus 5.6 months (95% CI, 5.6-5.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.85; P = .0001). In the atezolizumab arm, the 12-month PFS rate was 24.7% compared with 12% in the chemotherapy arm.

IMpower131 met its coprimary endpoint of investigator-assessed PFS with atezolizumab plus chemotherapy versus chemotherapy in the ITT population.

Treatment-related AEs of any grade occurred in 94.6% of patients in the atezolizumab arm versus 90.7% in the control arm.

The group that demonstrated the most benefit in terms of survival had high PD-L1 levels, explained Langer. OS continues to be followed, with the next interim OS analysis anticipated later in 2018.

“[IMpower131] is not the game changer, KEYNOTE-407 is,” Langer stated. “If there was any trial that should have been in the main plenary session [at the 2018 ASCO Annual Meeting] this was it. It was buried in a clinical science symposium that half of us didn’t get to, me included.”

KEYNOTE-407 is a first-line trial of pembrolizumab plus carboplatin plus paclitaxel or nab-paclitaxel in patients with metastatic squamous NSCLC. The trial results demonstrated that the addition of pembrolizumab to frontline chemotherapy reduced the risk of death by 36% compared with chemotherapy alone.⁷

Median OS with the addition of pembrolizumab was 15.9 months (95% CI, 13.2-not evaluable) versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49- 0.85; P = .0008). The PFS for the pembrolizumab group was 6.4 months (95% CI, 6.2-8.3) versus 4.8 months (95% CI, 4.3-5.7) with chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70; P <.0001). OS and PFS were observed regardless of PD-L1 status, but there was a correlation between an increase in PD-L1 level and a greater benefit.

Frequency and severity of AEs in both arms were similar, with observed events being consistent with known safety profiles of pembrolizumab/chemotherapy. No new safety signals were identified. Immune-mediated AEs were more frequent with pembrolizumab, but consistent with what has been seen with pembrolizumab monotherapy.

“Data suggest pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel should become a new standard of care for first-line treatment of metastatic squamous NSCLC, irrespective of PD-L1 expression,” Langer concluded.

Langer said that in the last 6 months, the changes in thoracic oncology have been unprecedented. These studies’ findings demonstrate that checkpoint inhibitors are active, often with durable responses, in platinum-refractory NSCLC.

References

1. Gentzler RD, Langer CJ, Borghai H, et al. 24-month overall survival from KEYNOTE-021 cohort G: Pemetrexed-carboplatin plus pembrolizumab as first-line therapy for advanced nonsquamous NSCLC. J Clin Oncol. 2018;36 (suppl; abstr 9026).
2. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
3. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
4. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36 (suppl; abstr 9002).
5. Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.
6. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. 2018;36 (suppl; abstr LBA9000).
7. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/ nab-paclitaxel (chemo) with or without pembrolizumab (pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105).