Expert Carefully Considers New Immunotherapy Combos in Nonsquamous NSCLC

Jared Weiss, MD

With the exception of the phase III KEYNOTE-042 trial, all of the pivotal phase III trials that have recently been reported in nonsquamous non—small cell lung cancer (NSCLC) have followed a similar formula by challenging the prior standard of care, chemotherapy, with the addition of a PD-1/PD-L1 inhibitor.

In a presentation during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Jared Weiss, MD, associate professor, Thoracic Oncology Program, University of North Carolina (UNC)-Chapel Hill, UNC Lineberger Comprehensive Cancer Center, discussed these trials in depth and their impact on the field.

In the phase III KEYNOTE-042 trial, treatment-naïve patients with stage IV nonsquamous PD-L1—positive NSCLC without an EGFR or ALK alteration were randomized to receive either pembrolizumab (Keytruda) monotherapy or platinum-based chemotherapy. Notably, crossover was not allowed in this trial.

“For this reason, it is even more important than usual that you not do the forbidden cross-trial comparison between single-agent pembrolizumab and any of the triplets that I talk about,” noted Weiss.

At the time of data cutoff in early 2018, the median overall survival (OS) in the intent-to-treat (ITT) population was 16.7 months with pembrolizumab and 12.1 months with chemotherapy, indicating a 19% reduction in the risk of progression or death with pembrolizumab (HR, 0.81; 95% CI, 0.71-0.93; P =.0018).¹ At 2 years, 39.3% of patients who received pembrolizumab were still alive versus 28.0% who received chemotherapy.

Once patients were stratified by a tumor proportion score (TPS) ≥50%, ≥20%, and ≥1%, it was clear that those with a TPS ≥50% derived the greatest clinical benefit from pembrolizumab with a hazard ratio of 0.69. These data mirrored those from the phase III KEYNOTE-024 trial, which served as the basis for the agent’s initial indication for use in patients with a TPS ≥50%. The benefit of pembrolizumab, although still present, diminished in patients with a TPS ≥20% and ≥1% with hazard ratios of 0.77 and 0.81, respectively.

When the survival curve for patients with a TPS ≤49% was presented in an exploratory analysis, the hazard ratio of 0.92 indicated a modest 1.3-month improvement in median OS with pembrolizumab, not reaching statistical significance.

“If we lived in a world without any of the triplet data, I might argue that in my clinic I might move over to single-agent immunotherapy for all my PD-L1—positive patients because while survival is comparable, toxicity is superior,” said Weiss. “However, we do live in a world that has triplets as an option.”

In the phase III KEYNOTE-189 trial, a similar patient population was randomized to receive pembrolizumab combined with standard platinum-based chemotherapy or platinum-based chemotherapy alone.

When pembrolizumab was added to pemetrexed and carboplatin, patients experienced a 51% reduction in the risk of progression or death compared with chemotherapy alone (HR, 0.49; 95% CI, 0.38-0.64; P <.001).² Similarly, in terms of progression-free survival (PFS), the risk reduction in progression or death was 48% (HR, 0.52; 95% CI, 0.43-0.64; P <.001).

Most notable were the length and linearity of the tail of the survival curve for both OS and PFS, commented Weiss.

“Some of you may be tired of us constantly talking about the tail, but it’s what every patient comes in asking for. They don’t come in asking us if we can give them a statistically significant chance of living an extra month early in their time,” he said. “They ask if they can be at their daughter’s wedding in a year and a half, and here we see a meaningful improvement in that outcome.”

Although a similar trend of added OS and PFS benefit with pembrolizumab was observed with a higher TPS score as was seen in the KEYNOTE-042 trial, a TPS <1% should not preclude patients from receiving the triplet regimen as a TPS ≤49% does for single-agent immunotherapy, added Weiss. In this context, PD-L1 negativity does not have enough negative predictive value to apply as a blanket biomarker.

In terms of the toxicity profile with the combination regimen, it’s additive and acceptable.

Subsequently, the phase III IMpower150 trial randomized patients to 1 of 3 treatment arms: platinum-based chemotherapy and atezolizumab (Tecentriq; arm A); platinum-based chemotherapy, bevacizumab (Avastin) and atezolizumab (arm B); or platinum-based chemotherapy and bevacizumab (arm C).

Data from a preliminary analysis demonstrated a median PFS of 8.3 months in arm B versus 6.8 months in Arm C, reflecting a 38% reduction in the risk of progression or death with the addition of atezolizumab to chemotherapy (HR, 0.62; 95% CI, 0.52-0.74; P <.001).³ At 1 year, 36.5% of patients in arm B and 18.0% of patients in arm C remained free from progression.

Although a PD-L1 analysis was done, it was restricted to the infiltrating T cells and tumor population, and was interpreted differently from the PD-L1 IHC 22C3 assay used in KEYNOTE-042. However, taken individually, it does shed considerable insight on the positive prognostic value of higher PD-L1 and T-effector signature expression, said Weiss. An additional analysis showed that the benefit of the quadruplet regimen was observed irrespective of biomarker subgroup, even in patients with EGFR and ALK alterations who, after exhausting all available targeted therapies, were eligible to enroll on the trial. These patients comprised approximately 10% of the ITT population.

“I am cautiously expanding my use [of the quadruplet regimen] in the EGFR and ALK population and probably now the RET population, if not all nonsmoking patients when they’re through with their targeted therapy,” said Weiss.

In terms of OS, although the data are still fairly immature, they demonstrate a prolonged survival with the addition of atezolizumab to chemotherapy and bevacizumab versus chemotherapy/bevacizumab alone (HR, 0.78; 95% CI, 0.64-0.96; P =.02).

The phase III IMpower132 trial echoed these findings following randomization to atezolizumab, pemetrexed, and physician’s choice of carboplatin or cisplatin compared with chemotherapy alone with a hazard ratio of 0.60 for PFS and 0.81 for interim OS.⁴

The similarly designed phase III IMpower130 trial took patients and randomized them to atezolizumab, carboplatin, and nab-paclitaxel (Abraxane) or carboplatin and nab-paclitaxel.⁵

“Nab-paclitaxel doesn’t require steroids, so there’s the theoretical advantage of better synergy with immunotherapy, as well as carboplatin, which can be used in patients with impaired renal function,” said Weiss.

Because pemetrexed is not indicated for patients whose glomerular filtration rates are above 40, this regimen can serve as an alternative to the IMpower132 regimen, with a median PFS of 7.0 months (HR, 0.64) and a median OS of 18.6 months (HR, 0.79).

“There’s a dizzying amount of parallel options out there,” said Weiss, and PD-L1, although an imperfect biomarker, does clarify whether single-agent immunotherapy is appropriate. Beyond that, toxicity and patient preference should be used to distinguish between available triplets and quadruplets.

References

1. Lopes G, Wu Y-L, 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. J Clin Oncol. 2018;36(suppl 18, abstr LBA4). doi: 10.1200/JCO.2018.36.18_suppl.LBA4.
2. Gandhi L, Rodríguez-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.
3. Socinski MA, Jotte RM, 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.
4. Papadimitrakopoulou V, Cobo M, Bordoni R, et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol. 2018;13(10):S332-S333. doi: 10.1016/j.jtho.2018.08.262.
5. Cappuzzo F, McCleod M, Hussein M, et al. IMpower130: progression-free survival (PFS) and safety analysis from a randomised phase III study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. Ann Oncol. 2018;29(suppl 8; abstr LBA53). doi: 10.1093/annonc/mdy424.065.