CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: June 26, 2024
Expiration: December 25, 2024
RATIONALE-315: Surgical Outcomes: Study Design
Luis Paz-Ares, MD, PhD:
The first 2 studies from ELCC 2024 that we will discuss are in the setting of early-stage NSCLC. Yue and colleagues1 presented an exploratory analysis of surgical outcomes with perioperative tislelizumab, an anti–PD‑1 agent, from the RATIONALE-315 trial. The European Medicines Agency recently approved 3 new indications for tislelizumab either as monotherapy or in combination with chemotherapy to treat various settings of advanced NSCLC.2
Earlier phase III trials had demonstrated that combining an immune checkpoint inhibitor (ICI) with neoadjuvant chemotherapy with or without adjuvant ICI monotherapy significantly improves rates of pathologic complete response (pCR), event-free survival (EFS), and OS for patients with resectable NSCLC.3-8
Consistent with these results, RATIONALE-315 demonstrated that adding tislelizumab to neoadjuvant chemotherapy followed by adjuvant tislelizumab significantly improved rates of major pathologic response (MPR), pCR, and EFS in Chinese patients with resectable NSCLC.1,9
In brief, this was a randomized, double-blind phase III trial at multiple sites in China (NCT04379635).1 Eligible patients had resectable stage II to IIIA NSCLC with good performance status (PS) and were wild-type for EGFR and ALK. The 453 participants were stratified by histology, disease stage, and PD‑L1 expression, and then randomized on a 1:1 basis to neoadjuvant platinum-doublet chemotherapy plus tislelizumab 200 mg Q3W or chemotherapy plus placebo. After 3 to 4 cycles, patients underwent surgery and were then treated with adjuvant tislelizumab 400 mg Q6W or placebo for up to 8 cycles.
As mentioned earlier, this analysis focuses on surgical outcomes. An earlier report observed that more patients who received chemoimmunotherapy underwent surgery vs those who received chemotherapy plus placebo (84.1% vs 76.2%, respectively).9 The phase III KEYNOTE-671 trial reported a similar outcome in patients who received perioperative pembrolizumab plus chemotherapy in this setting.4
RATIONALE-315 Surgical Outcomes: Baseline Characteristics
Luis Paz-Ares, MD, PhD:
Regarding demographics, 90% of the patients were male, 84% to 85% were current or former smokers, and all were Asian.1 Because the trial excluded patients with EGFR/ALK alterations—which are much rarer in squamous histology10—this tilted the population towards greater representation of squamous cell carcinoma, which was present in approximately 80% of patients.1 Approximately 60% of patients had stage IIIA disease. Of importance, approximately 40% of patients had PD‑L1 expression less than 1%.
RATIONALE-315 Surgical Outcomes: Surgical Delay by Disease Stage
Luis Paz-Ares, MD, PhD:
As you can see in this table, there was a slight increase in the time to surgery for patients treated with tislelizumab plus chemotherapy vs placebo plus chemotherapy.1 The median time from randomization to definitive surgery was 13.4 weeks vs 12.7 weeks, respectively. However, I would consider that a trivial increase.
Zofia Piotrowska, MD:
I found it reassuring that we saw no major differences in surgical delays between the arms.
RATIONALE-315 Surgical Outcomes: Surgical Approaches by Disease Stage
Luis Paz-Ares, MD, PhD:
The surgical approach data were quite important. As we can see here, open surgery was less common among patients treated with tislelizumab plus chemotherapy vs placebo plus chemotherapy (34% vs 41%, respectively), particularly among those with stage IIIA disease (36% vs 47%). More patients treated with tislelizumab were able to undergo minimally invasive surgery (60% vs 50% with placebo).
Of importance, as has been observed in some other trials, fewer patients treated with tislelizumab plus chemotherapy met the requirements for converting from minimally invasive surgery to thoracotomy. This was particularly the case for patients with stage IIIA disease (11% vs 7% with placebo plus chemotherapy).
RATIONALE-315 Surgical Outcomes: 90-Day Postoperative Complications
Luis Paz-Ares, MD, PhD:
There were no notable differences in the rates or types of postoperative complications between arms at 30 or at 90 days.1 The postsurgery mortality rates were also comparable.
The only difference was a small increase in frequency of incision site pain for patients treated with tislelizumab plus chemotherapy (41% vs 32% with placebo plus chemotherapy).
RATIONALE-315 Surgical Outcomes: Clinical Implications
Luis Paz-Ares, MD, PhD:
These data support tislelizumab as another PD‑1 agent that has significant benefit in the perioperative setting of NSCLC, at least for Asian patients.
We should note that this regimen has not been evaluated in Western populations. Rather than undertaking a full phase III trial, I would suggest performing a phase II trial assessing the noninferiority of perioperative tislelizumab plus chemotherapy vs an approved PD-1 agent plus chemotherapy, with a fast primary endpoint such as pCR. That could potentially support the use of this agent in Western countries.
I am being conservative and cautious in suggesting this noninferiority trial because other studies have found no differences with tislelizumab between Asian vs Western populations. For example, the phase III RATIONALE-303 trial demonstrated the efficacy of second-line tislelizumab for NSCLC and found that the benefits were comparable between the Asian White subgroups.11[Zhou 2022]
Zofia Piotrowska, MD:
I agree that these data provide further support for perioperative chemoimmunotherapy in resectable stage II-III NSCLC as our standard of care.
Although approved by the FDA for patients with previously treated esophageal squamous cell carcinoma, tislelizumab has not received an approval in this setting.12 Currently, the FDA has approved the pembrolizumab-based regimen from KEYNOTE-671 and the neoadjuvant approach with nivolumab from CheckMate 816 in this setting.13,14 Both regimens are now a standard of care for patients with resectable NSCLC.15
It is important to consider whether we would use chemoimmunotherapy in patients with actionable biomarkers. RATIONALE-315 excluded patients with EGFR or ALK alterations, consistent with data from the metastatic setting indicating no benefit from immunotherapy in EGFR- or ALK-altered NSCLC.16 Each of these oncogenes has an approved targeted therapy in the adjuvant setting, which should be our preferred approach.
That being said, we lack data for many other oncogenes. Because there can be some variability in responsiveness to immunotherapy between oncogenes, I would recommend having a case-by-case and gene-by-gene discussion with a tumor board to decide the best approach. For example, KRAS-driven NSCLC is as sensitive to immunotherapy as wild-type cancer, making it very reasonable to use chemoimmunotherapy for this oncogene.17,18 By contrast, data suggest that HER2-altered NSCLC is less sensitive to immunotherapy.19
In my experience, those are the challenging cases that we discuss in our tumor boards. With biomarkers such as HER2 and RET, we generally do not recommend chemoimmunotherapy. Our concern is that—extrapolating again from data on EGFR/ALK alterations—there may be increased toxicity when the patient receives a targeted therapy following immunotherapy, in addition to less benefit from the immunotherapy.20,21
PACIFIC-2: Study Design
Zofia Piotrowska, MD:
Our next study is PACIFIC-2, which I consider to be one of the most anticipated studies presented at ELCC 2024. An earlier press release indicated that this study was negative, which made many attendees interested in seeing the data.
To provide some context, the PACIFIC trial changed our standard of care several years ago by demonstrating that consolidation with durvalumab vs placebo after definitive concurrent CRT significantly improved both PFS and OS in patients with unresectable stage III NSCLC.22
However, PACIFIC only enrolled patients who did not experience disease progression on concurrent CRT. This excludes a notable proportion of patients, as 15% to 50% of real-world patients will not be eligible for consolidation durvalumab due to disease progression or AEs.23-27 Thus, the rationale for the PACIFIC-2 trial was to address this unmet need. The hope was that immunotherapy earlier in the treatment course with standard CRT would further reduce the risk of early disease progression.
PACIFIC-2 was designed as a randomized, placebo-controlled, double-blind phase III trial.28 Eligible patients had locally advanced, unresectable stage III NSCLC with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1.
The patients were randomized 2:1 from the time of their initial diagnosis to either an experimental arm, which added durvalumab to concurrent CRT followed by durvalumab consolidation, or to the control arm, which added placebo to concurrent CRT followed by placebo consolidation. The control arm does not reflect current standard of care because PACIFIC-2 was designed and initiated before OS results were available from PACIFIC, which made durvalumab consolidation the standard of care.
Patients received durvalumab every 4 weeks along with concurrent CRT. Those who did not have disease progression at 16 weeks then received consolidation durvalumab until disease progression. This is an important difference from the PACIFIC trial, where consolidation durvalumab was given only for 1 year.
The primary endpoint of PACIFIC-2 was PFS by blinded review.
Luis Paz-Ares, MD, PhD:
I agree that the control arm was outdated. Other than that, I considered the design to be very reasonable.
Zofia Piotrowska, MD:
It was notable that the investigators changed the duration of consolidation durvalumab from a defined period of 1 year to until disease progression. I am curious about their rationale for that change; perhaps they hoped that patients would have even greater benefit if they received consolidation for even longer.
In my experience, fewer real-world patients make it all the way through the 1 year of consolidation durvalumab compared to clinical trial participants. Many of my patients experience either significant immune-related adverse events (irAEs) or even less severe but still bothersome toxicities, such as chronic arthralgias and other toxicities that become problematic over time. Many patients are older and already have some baseline arthritis that becomes exacerbated with immunotherapy. We can manage this complication, but it is important to have a clear risk-vs-benefit discussion with the patient.
It will be interesting to see what the duration of treatment with immunotherapy was in PACIFIC-2, to get a sense for how long patients were able to stay on durvalumab.
PACIFIC-2: Baseline Characteristics
Zofia Piotrowska, MD:
This was a fairly sizable study. PACIFIC-2 randomized 219 patients to the durvalumab arm vs 109 patients to the control arm.28 The arms were fairly well matched, with a few key differences. The durvalumab arm had slightly more squamous histology (55.3% vs 47.7% with control) and T4 tumors (57.5% vs 48.6%, respectively). Both of these characteristics are associated with somewhat inferior outcomes, making these important differences to keep in mind as we look at outcomes.29,30
It is also important to note that PACIFIC-2 enrolled patients from somewhat different regions than PACIFIC.28,31 PACIFIC-2 enrolled patients from Asia, Eastern Europe, South America, and Central America, whereas PACIFIC enrolled patients from Western Europe, North America, Southeast Asia, and Japan.
PACIFIC-2: PFS by BICR (Primary Endpoint)
Zofia Piotrowska, MD:
The study did not meet its primary outcome.28 There was no significant improvement in median PFS, but we did see a numerical improvement of 13.8 months in the experimental arm vs 9.4 months in the placebo arm. However, the HR of 0.85 (95% CI: 0.65-1.12) was not statistically significant, with a P value of .247.
Of importance, Dr Bradley called out during his presentation that if we look at the first 6 months of treatment—which approximates the time when durvalumab was added to concurrent CRT—we do not see any separation between the curves. This suggests that early addition of durvalumab does not improve outcomes as much as we might have hoped.
We also saw that there was no difference in OS between the arms, as might be expected based on the lack of PFS benefit (HR for OS: 1.03; 95% CI: 0.78-1.39; P = .823).
PACIFIC-2: Safety
Zofia Piotrowska, MD:
There was a lot of interest in the safety profile of durvalumab combined with concurrent CRT. Overall, the rates of toxicities were fairly comparable between the arms.28 In particular, the rates of pneumonitis—whether called pneumonitis or radiation pneumonitis—were similar, with both arms reporting pneumonitis in 29% of patients. Fortunately, the rate of grade 3 or higher pneumonitis was fairly low at 4.6% in the durvalumab arm vs 5.6% in the control arm. That was certainly reassuring.
However, when we look at the AEs that led to discontinuation of durvalumab or placebo, we see a much higher rate of 25.6% in the durvalumab arm vs 12.0% in the control arm. This difference was particularly pronounced during the first 4 months of treatment, which covers when patients were on concurrent CRT with durvalumab or placebo. In the first 4 months, 14.2% of patients in the durvalumab arm vs 5.6% in the control arm experienced an AE leading to discontinuation of durvalumab or placebo.
PACIFIC-2: Time to Onset of AEs and Type of Fatal AEs
Zofia Piotrowska, MD:
Unfortunately, we also saw that there was a higher rate of AEs leading to death in that durvalumab arm vs the control arm, at 6.8% vs 4.6%, respectively.28 There was also a higher rate of grade 3/4 AEs during that initial 4 months of treatment when patients were receiving concurrent CRT (57.1% with durvalumab vs 52.8% with placebo). These are fairly small numbers, but still noteworthy with this treatment approach.
Returning to the deaths, these were attributed to infections/infestations; cardiac disorders; respiratory thoracic or mediastinal disorder; and injury, poisoning, and procedural complications. It is interesting that infections/infestations drove the differences in death rate (2.7% with durvalumab vs 0% with placebo). Infectious events are not usually considered part of the safety profile for ICIs. We would have to dive more into the data to understand potential reasons for this, such as differences in the rates of neutropenia and myelosuppression. I would also want to know what specifically was being called infection, whether there was overlap between an infectious process vs an autoimmune or inflammatory disorder, and how those were being adjudicated.
PACIFIC-2: Clinical Implications
Zofia Piotrowska, MD:
My takeaway is that these results were somewhat surprising. Many oncologists had hoped that adding durvalumab earlier in the treatment course would further improve outcomes in this population, given the benefit that we saw with adding consolidation durvalumab in PACIFIC. Unfortunately, adding immunotherapy to concurrent CRT was not beneficial in PACIFIC-2, and also led to some significant toxicities.
These data show that we should not change the current standard of care regimen from the PACIFIC trial. Patients with locally advanced, unresectable stage III NSCLC should continue to undergo concurrent CRT, should have repeat scans, and then be considered for consolidation durvalumab.
I hope that we will see more in-depth analyses from PACIFIC-2 to potentially identify any subpopulations who might have had PFS benefit, as we did see numerical improvement in that endpoint. I would also hope to better understand which patients were more likely to experience toxicities.
Dr Paz-Ares, can you comment on any areas of research that you consider particularly promising for improving the current standard of care with the PACIFIC regimen?
Luis Paz-Ares, MD, PhD:
Yes. Multiple ongoing trials have a similar study design as PACIFIC-2 or PACIFIC but are evaluating other ICIs either as monotherapy or in combination. Regimens under investigation include durvalumab in combination with either oleclumab, an anti-CD73 agent, or monalizumab, an anti-NKG2A agent (PACIFIC-9; NCT05221840); nivolumab with or without ipilimumab (CheckMate 73L; NCT04026412); and atezolizumab with tiragolumab (SKYSCRAPER-03; NCT04513925). We can look forward to seeing whether this strategy performs consistently across different trials.
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