CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 25, 2023
Expiration: August 24, 2024
Introduction: ES-SCLC and MPM
Karen Reckamp, MD:
We will finish with a discussion of highlights from other types of lung and thoracic cancers presented at ASCO 2023: phase II SWOG S1929, which evaluated PARP inhibition plus IO vs IO monotherapy in SLFN11-positive ES-SCLC, and phase III CCTG IND.227, which looked at platinum CT plus pemetrexed with or without pembrolizumab in untreated advanced MPM.
SWOG S1929: Study Design
Karen Reckamp, MD:
Despite initial response to induction therapy, most patients with ES-SCLC progress within 1 year of starting treatment, and responses after frontline therapy are rare.51 More recently, the addition of IO (atezolizumab or durvalumab) to first-line platinum-based CT and etoposide has improved patient outcomes.52,53 Atezolizumab was approved by the FDA in combination with carboplatin and etoposide for the first-line treatment of adult patients with ES-SCLC based on improved median OS vs carboplatin plus etoposide alone (12.3 months vs 10.3 months; HR: 0.76; 95% CI: 0.60-0.95; P = .0154) in the phase III IMpower133 trial.10,52 Durvalumab also is approved by the FDA in combination with etoposide and either carboplatin or cisplatin as first-line treatment of adult patients with ES-SCLC based on favorable OS data vs etoposide plus carboplatin or cisplatin (median OS: 12.9 months vs 10.5 months; HR: 0.71; 95% CI: 0.60-0.86; nominal P = .0003) from the phase III CASPIAN trial.37,53 Despite these advances, there remains an unmet need for additional treatments, especially with reduced toxicity.
The randomized, open label phase II SWOG S1929 trial looked at maintenance talazoparib (PARP inhibitor) plus atezolizumab vs atezolizumab alone in patients with SLFN11-positive ES-SCLC (N = 106).54 While receiving induction therapy with platinum CT and etoposide and atezolizumab, patients with ES-SCLC were tested for SLFN11 expression, a potential predictive biomarker for sensitivity to PARP inhibition.55 If positive, patients were randomized 1:1 to receive maintenance therapy with combination talazoparib plus atezolizumab or atezolizumab alone. Patients also were allowed to receive prophylactic cranial radiation or thoracic radiation, if indicated, prior to randomization. The primary endpoint for this study was PFS, with secondary endpoints of OS, ORR, and safety.
SWOG S1929: Baseline Characteristics
Karen Reckamp, MD:
In this study, we saw a typical small-cell lung cancer (SCLC) population, with a median age of 66.7 years, more male (56%) patients, and a majority of White (89%) patients, with 6% Black patients and 6% Hispanic patients.54 Zubrod performance status was mostly 0 1 (96%), and 25% of patients had prior thoracic radiation.
SWOG S1929: Best Response in Evaluable Patients
Karen Reckamp, MD:
We do not tend to see responses during maintenance therapy, and many patients had stable disease (47% in the atezolizumab plus talazoparib arm vs 53% in the atezolizumab arm).54 DCR was not significantly different at 59% in the combination arm vs 69% in the atezolizumab monotherapy arm.
SWOG S1929: PFS
Karen Reckamp, MD:
Patients who received talazoparib plus atezolizumab had significant improvement in PFS (4.2 months vs 2.8 months; HR: 0.70; 95% CI: 0.52-0.94; 1-sided log rank stratified P = .056) vs atezolizumab alone.54
SWOG S1929: PFS Subgroup Analysis
Karen Reckamp, MD:
PFS subgroup analysis revealed that patients who had prior RT had a better HR for talazoparib plus atezolizumab (0.54 vs 0.74) compared with those with no prior RT, and patients with brain metastases had a better HR (0.42 vs 0.75) compared with those with no brain metastases.54 Patients with no bone metastases also had a better HR than those who had bone metastases (0.61 vs 0.93). In analysis of PFS for liver metastases, the difference in HR was smaller at 0.60 for patients with no liver metastases and 0.77 for patients with liver metastases.
SWOG S1929: Preliminary OS
Karen Reckamp, MD:
Looking at the early OS data, there was a numerical but not statistically significant difference in OS (9.4 months vs 8.5 months; HR: 1.17; 95% CI: 0.80-1.71; P = .30) for the combination vs atezolizumab alone.54
SWOG S1929: Hematologic TRAEs
Karen Reckamp, MD:
As might be expected with a PARP inhibitor, more hematologic TRAEs were seen in patients receiving atezolizumab plus talazoparib, but the majority were grade 1-2.54 There was a significant increase in grade ≥3 hematologic TRAEs for the combination vs atezolizumab alone (50% vs 4%; P <.001). These grade ≥3 TRAEs included anemia (37% vs 2%) and decreases in white blood cell count (6% vs 0%), platelets (25% vs 0%), neutrophils (2% vs 0%), and lymphocytes (6% vs 2%).
SWOG S1929: Nonhematologic TRAEs
Karen Reckamp, MD:
Grade ≥3 nonhematologic TRAEs were seen in 15% of patients on the combination arm and 13% of patients on the atezolizumab arm.
SWOG S1929: Clinical Implications
Karen Reckamp, MD:
The remarkable aspect of SWOG S1929 is that it is one of the first prospective studies to select patients with SCLC for maintenance therapy. We are now in an era where selecting patients in SCLC is feasible, which in the past may not have been the case because of small biopsy samples. To demonstrate that a selective trial can be done in SCLC is a major step forward.
PFS was improved with addition of PARP inhibition, but neither group did as well as we might have expected, making it hard to know if this is the best therapy. Moving forward, we will have to consider the increased hematologic toxicities and decide whether that is worth the 2 month PFS benefit. It is important to keep this risk-to-benefit balance in mind, and in the future, patient reported outcomes will be key as we try to add to therapies and improve outcomes for our patients with SCLC, who desperately need better therapies.
Treatment of MPM
Heather Wakelee, MD, FASCO:
Finally, we are going to discuss an important update for our patients with MPM, a population with great unmet clinical need.
Platinum CT plus pemetrexed has been the SoC for MPM for decades, with a median OS of 12-13 months.56,57 For patients with unresectable disease, platinum CT plus pemetrexed may be combined with the antiangiogenic agent bevacizumab for first-line treatment followed by maintenance bevacizumab based on improved median OS vs platinum CT and pemetrexed alone (18.8 months vs 16.1 months; HR: 0.77; P = .0167) in the phase III MAPS trial.58,59
ICI-based treatments also have shown promise as treatment for MPM. Nivolumab is approved by the FDA for adult patients with unresectable MPM as first-line treatment in combination with ipilimumab.14,60 This approval was based on data from the phase III CheckMate-743 trial where nivolumab plus ipilimumab resulted in improved median OS (18.1 months vs 14.1 months; HR: 0.74; P = .002) compared with platinum CT plus pemetrexed.61 In previously treated MPM, treatment with pembrolizumab suggested antitumor activity (ORR: 20%; stable disease: 52% in patients with PD-L1–positive tumors).62
CCTG IND.227 : Pembrolizumab Plus CT vs CT in Treatment-Naive MPM
Heather Wakelee, MD, FASCO:
The CCTG IND.227 trial originally was designed as a phase II study in patients with untreated advanced MPM comparing platinum CT plus pemetrexed with or without pembrolizumab, with a pembrolizumab monotherapy arm. However, accrual to the pembrolizumab monotherapy arm was halted based on 16-week DCRs, and accrual to the other 2 arms was converted to a phase III trial.63
The primary endpoint was OS, with secondary endpoints including tolerability, response, PFS, and QoL. The results of the phase III CCTG IND.227 trial were presented at ASCO 2023.64
CCTG IND.227: Efficacy
Heather Wakelee, MD, FASCO:
The combination of pembrolizumab plus CT significantly improved median OS (17.28 months vs 16.13 months; HR: 0.79; 95% CI: 0.64-0.98; P = .0324) and median PFS (7.13 months vs 7.16 months; HR: 0.80; 95% CI: 0.65-0.99; P = .0372) vs CT alone.64 These differences are not always obvious at the beginning, but there is a clear separation over time. The ORR also was significantly higher with combination therapy vs CT alone (62% vs 38%; P <.0001). This was a positive trial that gives us new therapeutic options to explore for MPM.
CCTG IND.227: Clinical Implications
Karen Reckamp, MD:
I think it is exciting that we now have more options for patients with MPM. Platinum CT and pemetrexed with and without bevacizumab are recommended treatments, and now—in addition to nivolumab plus ipilimumab—pembrolizumab plus CT may be an option based on these data. We probably will be using combinations of these agents in the future.
Overall Takeaways
Heather Wakelee, MD, FASCO:
For me, the most exciting data at ASCO2023 in thoracic malignancies was for early-stage NSCLC. The OS data from ADAURA and the EFS data from KEYNOTE-671 and NEOTORCH are really compelling. The SoC for early-stage lung cancer is changing quickly. For advanced-stage NSCLC we unfortunately did not have anything that I would consider practice changing, but I will continue to watch the ADC data closely. In mesothelioma, I do think that the CT plus pembrolizumab approach is a new standard option for patients and was excited by those results.
Karen Reckamp, MD:
The most promising and practice-changing data at ASCO 2023 were the perioperative studies that have the potential to result in more cures for our patients. The DFS benefits with neoadjuvant and adjuvant IO for patients without actionable alterations and osimertinib with OS improvement as adjuvant therapy for patients with EGFR mutant NSCLC are major advances. I agree with Dr. Wakelee about the buzz surrounding ADCs which we hope will offer additional benefits for patients with advanced disease. Incremental steps forward for MPM and ES-SCLC at ASCO 2023 may lead to improved therapies for the future.
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