Checkpoint inhibition: subgroups, combination maintenance and retreatment

POSEIDON: impact of mutational status

The global, randomized, open-label, phase III POSEIDON trial was conducted to test the PD-L1 antibody durvalumab with or without the CTLA-4 inhibitor tremelimumab in addition to chemotherapy Q3W for 4 cycles compared to platinum-based chemotherapy Q3W for up to 6 cycles. Patients with stage IV NSCLC and EGFR/ALK wildtype who were treatment-naïve in the metastatic setting participated in POSEIDON. The combination regimens were followed by durvalumab Q4W until progression, with one additional tremelimumab dose in week 16 in the triple combination arm. Indeed, the combined administration of durvalumab, tremelimumab and chemotherapy gave rise to statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone [1].

According to growing insights into the prognostic and predictive significance of certain molecular aberrations, STK11– and KEAP1-mutated tumors convey poor prognosis, while the KRAS-mutant subgroup is heterogeneous and generally responsive to checkpoint inhibitor therapy, unless associated with co-mutations such as STK11 and KEAP1 [2, 3]. Therefore, Peters et al. performed an exploratory analysis of outcomes obtained in the POSEIDON study by STK11, KEAP1 and KRAS mutational status [4].

In the mutation-evaluable group with non-squamous histology included in the trial (n = 612), 14 %, 6 % and 30 % of patients had STK11, KEAP1 and KRAS mutations, respectively. Durvalumab/tremelimumab plus chemotherapy, as compared to chemotherapy alone, induced favorable trends for OS and PFS with generally longer median findings and higher 24-month rates across the molecularly defined groups, as well as higher overall response rates (ORRs) (Table). Responses obtained in the triple combination arm included complete remissions and were deeper and more durable than those in the control arm. Overall, these data suggested the use of durvalumab plus tremelimumab in addition to chemotherapy as a potential first-line option in harder-to-treat patient subgroups such as those with STK11, KEAP1 or KRAS mutations.

Table Clinical outcomes for durvalumab/tremelimumab plus chemotherapy (D/T + CT) vs. chemotherapy (CT) alone in patients with STK11, KEAP1 and KRAS mutations

Durvalumab/olaparib maintenance: ORION

In light of the need to further improve outcomes obtained with immunotherapy in metastatic NSCLC, the multicenter, double-blind, international, phase II ORION study evaluated durvalumab in combination with the PARP inhibitor olaparib as maintenance therapy. After first-line treatment with durvalumab Q3W plus platinum-based chemotherapy for 4 cycles, patients were randomized to either durvalumab Q4W plus olaparib (n = 134) or durvalumab plus placebo (n = 135) until progression.

The rationale of the study was based on the observation that increased DNA damage triggered through PARP inhibition might modify tumor immunogenicity and sensitize tumors to PD-(L)1 blockade, thus possibly promoting more durable responses than checkpoint inhibition alone [5, 6]. Investigator-assessed PFS was defined as the primary endpoint of the ORION trial.

According to the analysis reported at WCLC 2022, median PFS was numerically longer with the olaparib-based treatment than with durvalumab alone (7.2 vs. 5.3 months; HR, 0.76; p = 0.074) [7]. The results for the subgroups were generally consistent with the ITT analysis. Median OS was immature; the 12-month rates amounted to 65.6 % vs. 60.4 % (HR, 0.90; p = 0.604). Durvalumab plus olaparib was generally well tolerated, with no new safety concerns identified. The experimental arm experienced numerically higher rates of grade 3/4 AEs (34.3 % vs. 17.9 %), serious AEs (18.7 % vs. 14.2 %), and AEs leading to discontinuation of either study treatment (10.4 % vs. 4.5 %). Treatment-related deaths were reported in 0 % vs. 0.7 %.

The biomarker analyses demonstrated that the presence of homologous recombination repair (HRR) mutations did not enrich for activity in the experimental arm; median PFS with durvalumab plus olaparib was shorter in these patients compared to those with HRR wildtype tumors (3.9 vs. 7.4 months). Among patients with HRR wildtype, PFS favored the combination vs. durvalumab monotherapy. More­over, PFS was improved in the experimental arm compared to the control arm in the subgroups without PD-L1 expression (< 1 %) and with PD-L1 expression of 1-49 %. PFS in the cohort with PD-L1 ≥ 50 % did not differ across the arms; compared with the < 50 % subgroups, median PFS was numerically higher in both treatment groups.

However, the small sample sizes and numbers of events preclude definitive conclusions. As the authors noted, further research is required to assess the possible role of combination therapy with durvalumab and olaparib in metastatic NSCLC.

Pembrolizumab retreatment in 5 phase III trials

Single-agent pembrolizumab and pembrolizumab plus chemotherapy as first-line treatment substantially prolong OS and PFS compared to chemotherapy in advanced NSCLC without EGFR/ALK alterations [8-11]. In the clinical trial setting, patients whose disease progresses after the completion of 35 cycles of pembrolizumab have the potential to receive a second course for up to 17 additional cycles. An exploratory pooled analysis assessed the outcomes of patients who received second-course pembrolizumab after pembrolizumab monotherapy (Cohort 1) or pembrolizumab plus chemotherapy (Cohort 2). Cohort 1 included a total of 57 patients from the KEYNOTE-024, KEYNOTE-042 and KEYNOTE-598 trials, while Cohort 2 consisted of 14 patients from KEYNOTE-189 and KEYNOTE-407.

Rodríguez-Abreu et al. presented the results according to which a second course of pembrolizumab monotherapy is feasible and elicits clinically meaningful benefit [12]. Disease control during the second-course treatment was achieved in 73.7 % and 50.0 % in Cohorts 1 and 2, respectively. Cohort 1 contained only PD-L1–positive patients with PD-L1 expression ≥ 1 %. Here, the ORR was higher in the group with TPS 1-49 % (27.3 %) than in patients with TPS ≥ 50 % (17.4 %; Figure). Median duration of response had not been reached in Cohort 1 yet, and 78.8 % of patients responded for ≥ 6 months. Median OS was 27.5 months in Cohort 1 and had not been reached in Cohort 2. In both cohorts, 85.1 % of patients were alive at 6 months. Median PFS was 10.3 and 7.7 months, respectively, with 6-month rates of 60.8 % and 54.5 %, respectively.

The safety of the treatment proved manageable during the second course, with low rates of grade 3/4 treatment-related AEs (5 % and 7 %, respectively). Immune-mediated events were observed in Cohort 1 only; grade 1/2 and 3 AEs occurred in 9 % and 2 %, respectively. No treatment-related grade 5 events were reported in either cohort. These data support pembrolizumab retreatment upon disease progression in patients with advanced or metastatic NSCLC after completion of 35 cycles of first-course pembrolizumab with or without chemotherapy.

Figure: Overall response rates by PD-L1 expression during second-course pembrolizumab

Figure: Overall response rates by PD-L1 expression during second-course pembrolizumab


  1. Johnson M et al., Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study. J Thorac Oncol 2021; 16(10_suppl): S844
  2. Papillon-Cavanagh S et al., STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. ESMO Open 2020; 5(2): e000706
  3. Nakajima EC et al., Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. J Clin Oncol 40, 2022 (suppl 16; abstr 9001)
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  8. Reck M et al., Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375(19): 1823-1833
  9. Mok TSK et al., Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393(10183): 1819-1830
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