Immunotherapy Advances Drive Progress in Lung Cancer Treatment

Roy S. Herbst, MD, PhD

In the past 2 years, key data from clinical trials in advanced lung cancer have demonstrated that immunotherapy has expanded the bounds of the armamentarium for the treatment of several lung cancers. Clinical outcomes for patients without actionable mutations have shown that anti–PD-L1 agents provide results comparable or better than standard of care chemotherapy regimens.

In a presentation at the 19th Annual Winter Lung Cancer Conference by Roy S. Herbst, MD, PhD, chief of medical oncology and director of the Thoracic Oncology Research Program at Yale Cancer Center in New Haven, Connecticut, reviewed the trend toward chemotherapy-free options in the first line and the focus on exploring chemoimmunotherapy treatment pathways.¹

“[Lung cancer] is not Hodgkin’s Disease, it’s not a disease where the chemotherapy works so well where the cells apoptose and die,” Herbst said. “But I think we are seeing [progress with chemotherapy-free options] in metastatic disease and certainly in early disease.”

Immunotherapy Advances Fuel Drug Development

In a review of data from several studies, Herbst called attention to the baseline patient characteristics focusing on the role of PD-L1 expression on outcomes. For chemotherapy-naïve patients with advanced stage disease without targetable mutations, PD-L1 expression plays a role in determining treatment pathways.

“Immunotherapy is many things; [and it has] a very specific type of effect,” Herbst said. “Back 20 or 25 years ago, we knew about the T cell, we knew about MHC [major histocompatibility complex], we knew that the tumor cell presented a neoantigen and that interacted with the T cell. What’s new now is the whole idea of checkpoints.”

Starting with data from the phase 3 KEYNOTE-024 trial (NCT0214738), Herbst pointed to the efficacy of pembrolizumab (Keytruda) vs platinum-doublet chemotherapy in patients withmetastatic non–small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of at least 50%. Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks for 2 years and chemotherapy was given for 4 to 6 cycles. Patients who progressed after chemotherapy were allowed to crossover to the pembrolizumab arm.²

The primary end point of the trial was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR), and safety. Duration of response (DOR) was an exploratory end point. To be eligible for the trial, patients with untreated, stage IV NSCLC needed to have an ECOG performance status of 1 or less. Activating EGFR mutations or ALK translocations were not permitted. Patients with untreated brain metastases and/or active autoimmune disease requiring systemic therapy were not included.

Eligible patients (N = 305) were randomized 1:1 into the pembrolizumab or chemotherapy arms. Patients in the pembrolizumab group (n = 154) achieved a median OS of 26.3 months (95% CI, 18.3-40.4) compared with 13.4 months (95% CI, 9.4-18.3) in the chemotherapy group (HR, 0.62; 95% CI, 0.48-0.81). The 5-year OS rates were 31.9% vs 16.3%, respectively. The median PFS was 7.7 months (95% CI, 6.1-10.2) vs 5.5 months (95% CI, 4.2-6.2), respectively (HR, 0.50; 95% CI, 0.39-0.65). Three-year PFS rates were 22.8% vs 4.1%, respectively. The ORR in the pembrolizumab arm was 46.1% with a complete response (CR) rate of 4.5%, compared with 31.1% and no CRs in the chemotherapy group.

To further distill the efficacy of pembrolizumab in this patient population, investigators initiated the phase 3 KEYNOTE-042 study (NCT02220894) to asses pembrolizumab 200 mg every 3 weeks for up to 35 cycles (n = 637) vs standard-of-care (SOC) platinum-based chemotherapy for up to 6 cycles (n = 637). Patients needed to have a PD-L1 TPS of 1% or greater and an ECOG performance status of 0 or 1 to be eligible for the trial. The primary end point was OS in patients with a PD-L1 TPS at least 50%, at least 20%, and at least 1%.³

Patients who received pembrolizumab with a PD-L1 TPS of at least 50% (n = 73) had a median OS of 20.0 months (95% CI, 15.9-24.2) compared with 12.2 months (95% CI, 10.4-14.6) in the 85-patient chemotherapy group (HR, 0.68; 95% CI, 0.57-0.82). The median OS for patients with a PD-L1 TPS of at least 20% was 18.0 months (95% CI, 15.5-21.5) and 13.0 months (95% CI, 11.6-15.3) in the pembrolizumab (n = 75) and chemotherapy (n = 84) subgroups, respectively (HR ,0.75; 95% CI, 0.64-0.88). For patients with a PD-L1 TPS of at least 1%, the median OS was 16.4 months (95% CI, 14.0-19.6) in the 79-patient pembrolizumab cohort vs 12.1 months (95% CI, 11.3-13.3) in the 87-patient chemotherapy cohort (HR, 0.80; 95% CI, 0.71-0.90).

Beyond pembrolizumab, Herbst moved to data from other key trials that included agents in combination with targeted therapies.

MYSTIC (NCT02453282) was a phase 3 trial evaluating durvalumab with or without tremelimumab, a CTLA-4 antibody, compared with SOC platinum-based chemotherapy in patients with stage IV NSCLC irrespective of PD-L1 status. Patients were randomized 1:1:1 to receive durvalumab (Imfinzi) 20 mg every 4 weeks until disease progression (n = 374), tremelimumab 1 mg/kg every 4 weeks for up to 4 doses (n = 372) plus durvalumab until disease progression, or platinum-based chemotherapy (n = 372).⁴

Although statistical significance was not statistically significant, trends in OS among patients with PD-L1-positive tumor cells of at least 25%,favored durvalumab monotherapy over chemotherapy. Patients in this group who received durvalumab (n = 163) had a median OS of 16.3 months (95% CI, 12.2-20.8) vs 12.9 months (95% CI, 10.5-15.0) for the 162 patients treated with chemotherapy (HR, 0.76; 97.54% CI, 0.564-1.019; P = .036).

The phase 3 EMPOWER-Lung 1 study (NCT03088540) evaluated cemiplimab-rwl (Lybtayo) 350 mg monotherapy given intravenously every 3 weeks against 4 to 6 cycles of investigator’s choice chemotherapy in patients with untreated NSCLC with a PD-L1 expression of at least 50% on tumor cells and an ECOG performance status of 1 or lower. The trial randomized 710 patients 1:1 into the treatment arms. The primary end points of the trial were OS and PFS; secondary end points included ORR and DOR.⁵

In the intention-to-treat (ITT) population, the median OS was 22.1 months (95% CI, 17.7-not evaluable [NE]) in the cemiplimab arm (n = 356) vs 14.3 months (95% CI, 11.7-19.2) in the 354-patient chemotherapy group (HR, 0.68; 95% CI, 0.53-0.87; P = .0022). Among patients in the PD-L1 of at least 50% ITT population, the median OS was not reached (95% CI, 17.9-NE) compared with 14.2 months (95% CI, 11.2-17.5) in the cemiplimab and chemotherapy cohorts (HR, 0.57; 95% CI, 11.2-17.5).

Finally, Herbst called attention to data from the IMpower110 (NCT02409342) trial. The phase 3 clinical trial evaluated atezolizumab at a dose of 1200 mg every 3 weeks vs platinum-based chemotherapy in patients with chemotherapy-naïve, stage IV NSCLC displaying PD-L1 expression. Patients in the experimental arm continued treatment until disease progression or loss of clinical benefit and those in the control arm continued until disease progression. The primary end point was OS in the wild-type (WT) population.⁶

Among patients expressing TC3 or IC3 WT, the median OS was 20.2 months (95% CI, 17.2-27.9) and 14.7 months (95% CI, 7.4-17.7) in the atezolizumab (n = 107) and chemotherapy (n = 98) arms, respectively (HR, 0.76; 95% CI, 0.54-1.09). The 12-month OS rate among the atezolizumab group was 66.1% (95% CI, 57.1%-75.1%) compared with 52.3% (95% CI, 42.2%-62.4%).

Without the adverse effect profile of chemotherapy, immunotherapy treatment options provide more manageable therapeutic options for patients with advanced disease.

Chemotherapy Combinations

With the success as monotherapy treatment options, Herbst noted that the rationale for combining immunotherapy with chemotherapy has the potential to be a pillar of care for patients. Herbst cited the separate mechanisms of action of chemotherapy and immunotherapy can synergize to reduce T-cell inhibitory substances produced by tumor and alters tumor barriers to allow for T-cell penetration.

“Combination therapy reduces tumor bulk and leads to a separate mechanism of kill,” Herbst said. “Chemotherapy and immunotherapy are perhaps at least additive. It reduces T-cell inhibitory substances, alters tumor barriers, it kills tumor cells in a manner that might increase their immunogenicity, and it alters T-cell signaling. It’s like a reset, you’re resetting the tumor—it’s a shotgun approach. Someday, we’ll be a little more [precise] and will know exactly what we want to inhibit in the microenvironment.”

KEYNOTE-189 (NCT02578680) is a phase 3 trial of first line pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with stage IV non-squamous NSCLC. Patients must have an ECOG performance status of 1 or less and no actionable EGFR or ALK mutations to be eligible. The primary end points of the trial are OS and PFS; secondary end points consist of ORR, DOR, and safety.^7,8

Patients in the experimental arm (n = 406) are treated with pembrolizumab 200 mg and chemotherapy every 3 weeks. The control arm (n = 206) follows the same dosing schedule, replacing pembrolizumab with placebo. Patients remain on study until disease progression or unacceptable toxicity, with crossover from placebo allowed.

Median OS was not reached (95% CI, NE-NE) in the combination group vs 11.3 months (95% CI, 8.7-15.1) in the placebo arm (HR, 0.49; 95% CI, 0.38-0.64; P < .00001). Median PFS was 8.8 months (95% CI, 7.6-9.2) and 4.9 months (95% CI, 4.7-5.), respectively (HR, 0.52; 95% CI, 0.43-0.64; P < .00001). The ORRs were 47.6% and 18.9%, respectively.

The phase 3 IMpower 150 study (NCT02366143) examined atezolizumab and bevacizumab alone and together in combination with chemotherapy in patients with stage IV or recurrent metastatic non-squamous NSCLC. Atezolizumab was given at a dose of 1200 mg intravenously every 3 weeks in combination with chemotherapy (n = 402) and in combination with bevacizumab and chemotherapy (n = 400). There was also a bevacizumab plus chemotherapy arm (n = 400).⁹

Concerning the coprimary end point of PFS, the atezolizumab and bevacizumab plus chemotherapy group had a median of 8.3 months (95% CI, 7.7-9.8) compared with 6.8 months (95% CI, 6.0-7.1) in the and bevacizumab plus chemotherapy group (HR, 0.59; 95% CI, 0.50-0.70; P < .0001). The follow-up was approximately 20 months and the 12-month PFS rates were 38% and 20%, respectively.

Atezolizumab and bevacizumab plus chemotherapy also outperformed bevacizumab plus chemotherapy in the other coprimary end point of OS. Median OS was 19.2 months (95% CI, 17.0-23.8) and 14.7 months (95% CI, 13.3-16.9), respectively (HR, 0.78; 95% CI, 0.64-96; P = 0.164). The 18-month OS rates were 53% and 41%, respectively.

Additionally, atezolizumab and bevacizumab plus chemotherapy was shown to increase OS regardless of PD-L1 expression status. Patients who were PD-L1 high (TC3 or IC3) achieved a median OS of 25.2 months when treated with atezolizumab and bevacizumab plus chemotherapy (n = 71) vs 15.0 months in the 65-patient bevacizumab plus chemotherapy subgroup (HR, 0.70; 95% CI, 0.43-1.13). Among the PD-L1 low patients (TC1/2 or IC1/2), median OS was 20.3 months (n = 121) and 16.4 months (n = 105), respectively (HR, 0.80; 95% CI, 0.55-1.15). PD-L1 negative patients experienced a median OS of 17.1 months (n = 167) and 14.1 months (n = 177), respectively (HR, 0.82; 95% CI, 0.62-1.08).

References

1. Herbst RS. Immunotherapy chemo combinations vs monotherapy. Presented at: 19th Annual Winter Lung Cancer Conference. February 4-6, 2022; Miami Beach, FL.
2. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. LBA51 - KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325
3. Cho BC, Wu YL, Lopes G, et al. KEYNOTE-042 3-year survival update: 1L pembrolizumab vs platinum-based chemotherapy for PD-L1+ locally advanced/metastatic NSCLC. Presented at: 2020 World Conference on Lung Cancer Singapore. January 27-31, 2021. Abstract FP13.04.
4. Rizvi N, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann Oncol. 2018;29(suppl 10):X40-X41. doi:10.1093/annonc/mdy493
5. Sezer A, Kilickap S, Gümüş M, et al. LBA52 - EMPOWER-Lung 1: phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. Ann Oncol. 2020;31(suppl 4): S1142-S1215. doi:10.1016/annonc/annonc325
6. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC. N Engl J Med. 2020;383(14):1328-1339. doi:10.1056/NEJMoa1917346
7. 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
8. Rodríguez-Abreu D, Powell ST, Hochmair M, et al. Final analysis of KEYNOTE-189: pemetrexed-platinum chemotherapy (chemo) with or without pembrolizumab (pembro) in patients (pts) with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9582. doi:10.1200/JCO.2020.38.15_suppl.9582
9. Socinski MA, Jotte RM, 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 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002