CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: September 25, 2020
Expiration: September 24, 2021
Stephen V. Liu, MD
Two important randomized phase III trials evaluating dual checkpoint blockade in patients with newly diagnosed advanced EGFR and ALK wild‑type NSCLC were presented at ASCO 2020, including a 3‑year update from Part 1 of the CheckMate 227 study comparing the PD-L1 antibody nivolumab, with or without the CTLA-4 antibody ipilimumab, to histology-based chemotherapy9-11 and OS data from CheckMate 9LA evaluating nivolumab and ipilimumab in combination with 2 cycles of platinum-based chemotherapy vs chemotherapy alone.12
On May 15, 2020, nivolumab plus ipilimumab was approved by the FDA as a first-line treatment for patients with metastatic NSCLC and PD-L1 expression ≥ 1% who have no EGFR or ALK aberrations, followed by the regulatory approval on May 26, 2020, of nivolumab/ipilimumab plus 2 cycles of platinum-based chemotherapy, which was before public presentation of the CheckMate 9LA data at ASCO (a first to my knowledge).13
Let’s discuss the data reported for these 2 studies and explore what the results mean for clinical practice.
Stephen V. Liu, MD
CheckMate 227 (N = 1739) had a complex design.11 In Part 1a (n = 1189), patients with at least 1% PD-L1 expression were randomized 1:1:1 to combination nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) vs nivolumab alone (240 mg every 2 weeks) vs histology-based chemotherapy alone. In part 1b (n = 550), patients with less than a 1% PD-L1 expression 1% were randomized 1:1:1 to nivolumab/ipilimumab at the same dosages as part 1a vs nivolumab 360 mg every 3 weeks in combination with histology-based chemotherapy vs chemotherapy alone. Immunotherapy was administered for up to 2 years. The study had dual primary endpoints of PFS in patients with a high tumor mutational burden (≥ 10 mut/Mb) and OS in patients with at least 1% PD-L1 expression.
Previous reports on CheckMate 227 showed that nivolumab plus ipilimumab achieved a PFS benefit in patients with a high tumor mutational burden, with a median PFS of 7.2 months vs 5.5 months with chemotherapy (HR: 0.58; P < .001) and a 1-year PFS rate of 42.6% vs 13.2%, respectively.10 In results presented in 2019 at ESMO, OS also was shown to be significantly improved with dual immune checkpoint inhibition for patients with at least 1% PD-L1 expression (a coprimary endpoint), with a median OS of 17.1 months vs 14.9 months for chemotherapy (HR: 0.79; P = .007), leading to its aforementioned approval.9
At ASCO 2020, Ramalingam and colleagues presented updated 3-year efficacy and safety results for CheckMate 227.11 In my opinion, these types of updates are critical for trials evaluating immunotherapy-based treatments because their appeal as a therapeutic modality is their durability. Clinicians need the reassurance that benefit is maintained over time and that the survival tail remains flat, which as we will discuss, this update of CheckMate 227 provides for nivolumab plus ipilimumab.
Stephen V. Liu, MD
Consistent with earlier results, there continued to be a substantial OS benefit with combination immunotherapy in patients with PD-L1–positive NSCLC (median OS: 17.1 months vs 14.9 months with chemotherapy; HR: 0.79). Even more compelling was the duration of response achieved with the dual-antibody combination. In the PD-L1–positive group, the median duration of response was 23.2 months (95% CI: 15.2-32.2) vs only 6.7 months for chemotherapy (95% CI: 5.6-7.6)—a response of almost 2 years is quite remarkable.
Of importance, there was also a suggested OS benefit for the combination in patients with PD-L1–negative tumors (median OS: 17.2 months vs 12.2 months with chemotherapy; HR: 0.64), which is a patient population in great need of better treatment options. The larger survival benefit in the PD-L1–negative group compared with the group with PD-L1–positive disease was driven by the control arm, which showed a lower median OS with chemotherapy for the PD-L1–negative group at 12.2 months vs 14.9 months for the PD-L1–positive group, whereas the median survival with nivolumab plus ipilimumab was the same for both groups at approximately 17 months.
Stephen V. Liu, MD
When we look at landmark OS by response at 6 months in the PD-L1–positive group, the 3‑year OS rate in those with a CR or PR was 70% with the combination vs 39% with chemotherapy. These data were even more striking for patients with PD-L1–negative disease, with a 3-year OS rate in responders of 82% vs only 25% with chemotherapy.
Stephen V. Liu, MD
The nivolumab/ipilimumab regimen used in CheckMate 227 is chemotherapy free, but that does not mean that it is toxicity free. The overall rate of grade 3/4 AEs was 33% for the combination vs 36% with chemotherapy, and all-grade AEs led to discontinuation in 18% vs 9% of patients, respectively. Toxicity markedly decreased after 6 months, but there were no new safety signals from this combination overall (minimum follow-up: 36.3 months).
Stephen V. Liu, MD
The combination of nivolumab plus ipilimumab has emerged as yet another option for patients with treatment-naive advanced NSCLC, with the updated data from CheckMate 227 supporting the potential for long‑term survival and quite durable responses with this regimen.
Dr. Piotrowska, what are your thoughts on how this regimen will fit into your treatment algorithm?
Zofia Piotrowska, MD, MHS
I think it's always great to have options for our patients, and as you nicely highlighted, what really stands out about this regimen is the durability of the responses in the patients who do respond. In my clinical practice, I have had patients who had to discontinue this regimen for toxicity, but even they still experienced a durable response to treatment.
However, I think the challenge with this study relates to the PD-L1–negative population in which we already have a very good standard of care in the KEYNOTE-189 regimen of carboplatin/pemetrexed/pembrolizumab.[14]
Although nivolumab plus ipilimumab has not been compared head to head with the KEYNOTE-189 regimen, the toxicities associated with dual checkpoint inhibition are noteworthy, so for my PD-L1–low or PD-L1–negative patients who are eligible, I typically choose chemoimmunotherapy. This dual PD-L1 inhibitor combination, however, could be an option for those who are chemotherapy resistant or otherwise ineligible.
I wish we had a better prognostic biomarker to identify which patients are likely to respond to nivolumab/ipilimumab, and which ones are likely to have a durable response. Unfortunately, tumor mutational burden does not seem to be the be-all and end-all of patient selection for this therapeutic combination that we hoped it would be.
Stephen V. Liu, MD
There is almost an embarrassment of riches in terms of first-line immunotherapy options for advanced NSCLC, and choosing among them becomes a real challenge. As I mentioned, to me the most compelling use for this combination is in the PD-L1–negative group, albeit off label. This is where I am using this regimen most in clinical practice, but we will see if that changes over time.
One potential advantage to using nivolumab/ipilimumab upfront is that the second‑line option becomes platinum-doublet chemotherapy, whereas, if chemoimmunotherapy was used as first-line treatment, the second‑line treatment would be a docetaxel‑based regimen. This may be something to consider going forward.
However, at this time, while we await long-term survival data to reveal which regimens lead to a greater 5-year or 10-year survival rate, which we don’t have a good surrogate for yet, treatment must be individualized and modified in response to emerging data.
Zofia Piotrowska, MD, MHS
I very much agree.
Stephen V. Liu, MD
Building on the success of CheckMate 227 is CheckMate 9LA.The hypothesis for this study was that adding 2 cycles of a platinum-doublet chemotherapy to the combination of nivolumab/ipilimumab for first-line treatment of patients with advanced NSCLC could further improve the durable OS benefit seen in earlier CheckMate studies with this regimen.
In CheckMate 9LA, patients with newly diagnosed stage IV or recurrent NSCLC and wildtype EGFR and ALK (N = 719) were randomly assigned to the combination of nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks for up to 2 years with an initial 2 cycles of chemotherapy every 3 weeks or to the control arm of 4 cycles of chemotherapy every 3 weeks without immunotherapy.12 Chemotherapy selection was based on histology, and patients with nonsquamous disease in the chemotherapy-alone arm could receive pemetrexed as maintenance therapy. The primary endpoint was OS. Secondary endpoints included PFS, ORR, and efficacy by PD-L1 expression level.12
Stephen V. Liu, MD
CheckMate 9LA was a positive trial showing an OS improvement for the study regimen vs chemotherapy alone. In an interim analysis at a minimum follow-up of 8.1 months, the median OS was 14.1 months with nivolumab/ipilimumab plus chemotherapy vs 10.7 months with chemotherapy alone (HR: 0.69; 95% CI: 0.55-0.87; P = .0006). In an updated analysis with a minimum follow-up of 12.7 months, the median OS was 15.6 months with the study regimen vs 10.9 months with chemotherapy alone (HR: 0.66; 95% CI: 0.55-0.80). At 12 months, 63% of patients receiving chemoimmunotherapy remained alive vs 47% in the chemotherapy-only arm.
Stephen V. Liu, MD
The OS benefit with nivolumab/ipilimumab plus chemotherapy was seen across all major subgroups analyzed, including those with squamous histology, a group that has historically performed less well in other studies. It is reassuring to see meaningful benefit in this group (median OS: 14.5 vs 9.1 months with chemotherapy; HR: 0.62).
Stephen V. Liu, MD
The median PFS was also improved with nivolumab/ipilimumab plus chemotherapy (6.7 vs 5.0 months for chemotherapy alone; HR: 0.68). When looking at PFS data it is important to consider the shape of the curves: The PFS curves here show an initial dip in PFS within the first 3 months, which is typical with the use of immunotherapy alone. In CheckMate 227, the PFS curves for nivolumab and ipilimumab actually crossed initially before separating.11 In CheckMate 9LA, however, the curves did not cross; instead, they tracked together for the first 3 months and then separated over time.
Stephen V. Liu, MD
The ORR with chemoimmunotherapy was robust at 38% vs 25% with chemotherapy alone, with a duration of response of 11.3 months vs 5.6 months, respectively. There is a good tail to the duration of response curves. These data are immature, however, and I expect these numbers to improve with time.
Stephen V. Liu, MD
As expected, there was more toxicity with the combination chemoimmunotherapy regimen with a 47% incidence of grade 3/4 treatment-related AEs leading to discontinuation in 16% of patients. However, chemotherapy alone was also associated with a 38% rate of grade 3/4 treatment-related AEs, with 5% of patients discontinuing as a result. The most common treatment-related AEs were nausea, anemia, asthenia, and diarrhea, occurring in at least 15% of patients. With the chemotherapy in the chemoimmunotherapy arm limited to just 2 cycles there was, overall, less myelosuppression, which likely reflects the lack of cumulative bone marrow toxicity associated with this regimen.
Stephen V. Liu, MD
Here again is another new option for our patients with advanced NSCLC. The combination of dual checkpoint inhibition and chemotherapy potentially offers the advantages of both approaches as evidenced by the higher response rates. Furthermore, by adding chemotherapy, the initial PFS drop in the first 3 months with nivolumab/ipilimumab is avoided, perhaps by addressing hyperprogression.15 Although these data show impressive OS and duration of response, it is also clear that the combined toxicities in the chemoimmunotherapy arm are more worrisome than chemotherapy alone. Because of this, I have not yet incorporated this regimen into my practice.
Have you found a place for this in your algorithm, Dr. Piotrowska?
Zofia Piotrowska, MD, MHS
Not yet. I agree that its toxicity is noteworthy. At the same time, using only 2 chemotherapy cycles early in treatment may help avoid early progression and help provide a longer-term benefit from the immunotherapy. Realistically, however, I am not sure that I see a place for it in my clinical practice right now. As discussed, I think biomarkers are going to be critically important going forward to help identify which patients are most likely to benefit from each strategy.
Stephen V. Liu, MD
Although we have good outcomes with frontline immunotherapy-based regimens in our patients with advanced NSCLC, there is still certainly room for improvement. The phase II CITYSCAPE study reported at ASCO 2020 introduced a novel agent called tiragolumab, a TIGIT antibody, that we hope will complement the activity of available anti–PD-L1/PD-1 antibodies. TIGIT is an important checkpoint that is often coexpressed with PD-L1, and previous data from early studies in solid tumors demonstrated that tiragolumab is well tolerated as monotherapy and in combination with atezolizumab.16
In the randomized, double-blind, placebo-controlled phase II CITYSCAPE study, the combination of tiragolumab plus atezolizumab was compared with placebo plus atezolizumab as first-line therapy in patients with stage IV NSCLC, wild-type EGFR and ALK, and PD-L1 tumor proportion score greater than 1% (N = 135).17 Patients were randomized to tiragolumab 600 mg every 3 weeks plus atezolizumab 1200 mg every 3 weeks or to placebo plus atezolizumab at the same respective dosages. Treatment continued until loss of benefit or disease progression. The co-primary endpoints were ORR and PFS, with secondary endpoints of response duration, OS, safety, and patient-reported outcomes.
Stephen V. Liu, MD
The results from the updated analysis, with a median follow-up of 10.9 months, were quite impressive. The addition of tiragolumab to atezolizumab significantly improved ORR from 21% to 37% in the ITT population (N = 135). In the subgroup with high PD-L1 expression (n = 58), there was an even more dramatic improvement from 24% to 66%, which most likely reflects co-expression of TIGIT with PD-L1.
Stephen V. Liu, MD
PFS was also significantly improved in the ITT population (median PFS: 5.5 months with tiragolumab/atezolizumab vs 3.88 months with placebo/atezolizumab; HR: 0.58; 95% CI: 0.38-0.89). The PFS benefit for patients with high PD-L1 expression was even more impressive with an HR of 0.30, an immediate and fairly impressive split in the PFS curves, and the suggestion of a robust tail to the curve in the tiragolumab arm. In this group, the median PFS was not reached in the tiragolumab arm vs 4.11 months with atezolizumab plus placebo.
These data are fairly immature, this is a modest-sized study, and it is worth noting that the control arm did not perform as is typically seen. Still, we did see a notable improvement in response and PFS for the PD-L1–high subgroup with the addition of this novel immunomodulator to immune checkpoint inhibition.
Stephen V. Liu, MD
Addition of tiragolumab to atezolizumab did elicit more toxicity; in particular, there was a higher incidence of immune-mediated AEs (69% vs 47% with the addition of placebo). However, these were primarily low grade and the rates of grade 3/4 immune-mediated AEs were lower at 18% vs 13%, respectively.
Immune-mediated rash was seen in a significant number of patients in the tiragolumab arm, but was primarily grade 1. Grade 1/2 infusion-related reactions and hypothyroidism were also fairly common. Of the patients who experienced pancreatitis, most events were grade 3/4.
Rates of treatment discontinuation were similar between arms at 10% and 9%, respectively. However, more AEs leading to dose modification or interruption occurred in the tiragolumab/atezolizumab arm (40% vs 28% in the placebo arm).
Stephen V. Liu, MD
Multiple immunotherapy combination regimens have been evaluated in this setting, but none have generated significantly better results than PD-1/PD-L1 antibodies alone. With CITYSCAPE we see a fairly significant improvement in response rate and PFS, especially in the PD-L1–high population—if these prove durable, I think tiragolumab/atezolizumab could significantly improve outcomes for these patients. However, this will need to be confirmed in large, randomized phase III studies, such as the SKYSCRAPER-01 study, which is evaluating the addition of tiragolumab to atezolizumab as first-line therapy in patients with locally advanced and unresectable, or metastatic PD-L1–selected NSCLC.18
I also think this strategy is a smart one. Overcoming acquired resistance to checkpoint inhibitors is very challenging because the mechanisms of resistance are heterogeneous, so using these drugs upfront to improve initial responses may prove to be a more viable long-term strategy.
What are your thoughts on these data, Dr. Piotrowska?
Zofia Piotrowska, MD, MHS
I was excited to see them. For years, we have been hearing rumblings about newer immunotherapy compounds to join the PD-1/PD-L1 and CTLA-4 inhibitors we’ve been using for years, but this is one of the strongest signals to date for an emergent novel immunotherapy target, and may actually improve outcomes. As you said, the data are early and the study size is modest, but to see that degree of improvement in a randomized phase II study is certainly intriguing. I will definitely be keeping an eye out for future reports on tiragolumab going forward.
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