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Key Studies in NSCLC: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Zofia Piotrowska, MD, MHS
Karen L. Reckamp, MD, MS
Released: August 20, 2021

Advances in Metastatic NSCLC—Immunotherapy

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: Study Design

Karen L. Reckamp, MD, MS:
Now we will turn our attention to advances in immunotherapy in metastatic NSCLC presented at ASCO 2021. Again, we saw numerous updates of important studies that have been previously reported, with the exception of the pooled analysis that we will discuss first.

The pooled analysis of first‑line combination chemotherapy plus immunotherapy (chemo-IO) vs immunotherapy alone in patients with advanced NSCLC looked specifically at the patient population with PD-L1 expression 1% to 49%, a subgroup for which treatment decisions can be challenging. This study was performed by the FDA, which had access to the primary data for the randomized, controlled clinical trials leading to approval of the first-line immunotherapy options we have today in the clinic for patients with advanced NSCLC. For immunotherapy alone, they included the KEYNOTE‑042 and CheckMate 227 trials. For combination chemo-IO, they included the KEYNOTE‑189, KEYNOTE-407, KEYNOTE-021 (cohort G), IMpower150, IMpower130, and CheckMate 9LA trials.23

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: Patient Characteristics

Karen L. Reckamp, MD, MS:
In this pooled analysis, more than half of the patients were younger than 65 years of age, and one third were female. Two thirds of the patients had nonsquamous histology and the majority had stage IV disease.23

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: Exploratory OS

Karen L. Reckamp, MD, MS:
An exploratory analysis of OS showed a survival benefit with chemo-IO vs immunotherapy alone in patients with PD-L1 expression 1% to 49%.23 This is consistent with what we know about these drugs and with results we have previously seen for this patient subgroup, but it is helpful to see it hold true in the pooled analysis.

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: OS Across Subgroups

Karen L. Reckamp, MD, MS:
When looking at OS across subgroups, we see that the survival benefit with chemo-IO vs immunotherapy alone seen in the overall population extends to the majority of subgroups analyzed. However, it appears that this benefit is lost for patients aged 75 years or older, with the caveat that this was the smallest group analyzed. Of note, this is a population for whom we often consider giving immunotherapy alone to mitigate toxicity from chemotherapy. Furthermore, patients who have never smoked may do better with chemo-IO, but there is a broad CI for that group of patients.23

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: Exploratory PFS

Karen L. Reckamp, MD, MS:
In an exploratory analysis of PFS, there was again a benefit in patients with PD-L1 expression 1% to 49% receiving chemo-IO vs immunotherapy alone.23  

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: PFS Across Subgroups

Karen L. Reckamp, MD, MS:
Then looking at the forest plot for PFS, again we see that patients aged 75 years or older potentially have less benefit with the combination chemo-IO.23  

FDA Pooled Analysis of First-Line Chemo-IO vs IO in Adv NSCLC With PD-L1 1% to 49%: Clinical Implications

Karen L. Reckamp, MD, MS:
The bottom line for me with this analysis is that it demonstrates that patients with PD-L1 expression 1% to 49% do need chemo-IO rather than immunotherapy alone. However, it also shows that there’s still a population who can benefit from single-agent immunotherapy—namely our elderly patients, for whom the toxicity of chemotherapy may be greater.

Zofia Piotrowska, MD, MHS:
I completely agree. No big surprises here. However, I think we often struggle with what to do for our patients with low PD-L1 expression, our elderly patients, and maybe even our more frail patients, so I appreciate that this analysis gives us some real data to support that immunotherapy alone, which we know is generally better tolerated than chemo-IO, is a reasonable option in these older, chemotherapy-ineligible patients who might not otherwise be able to withstand treatment.

Karen L. Reckamp, MD, MS:
I also think it would be interesting and informative to look at the chemotherapy arms in these trials, as was brought up during the discussion of this analysis at ASCO.

Zofia Piotrowska, MD, MHS:
Absolutely. There are definitely a variety of toxicities with chemotherapies, but some patients may do fine with chemotherapy alone.

CheckMate 227 Part 1 4-Year Update: Study Design

Karen L. Reckamp, MD, MS:
We’ll now discuss 2 updates of the CheckMate trials evaluating the combination of nivolumab and ipilimumab for the treatment of advanced NSCLC. First, we’ll discuss the 4-year update of the phase III CheckMate 227 trial part 1, which originally led to the approval of nivolumab/ipilimumab for first-line treatment of adult patients with metastatic NSCLC, tumor PD-L1 ≥1%, and no EGFR or ALK genomic aberrations. Next, we’ll look at the 2-year update of the phase III CheckMate 9LA trial, which originally supported the FDA approval of first-line nivolumab/ipilimumab and 2 cycles of platinum-doublet chemotherapy for the treatment of adults with metastatic NSCLC and no EGFR/ALK genomic tumor aberrations regardless of PD-L1 expression.24-25

Shown here is the complex study design for CheckMate 227 part 1 evaluating nivolumab/ipilimumab vs chemotherapy vs nivolumab alone as first-line treatment of advanced NSCLC without EGFR/ALK alterations.26 In this study, there were dual primary endpoints for the comparison of nivolumab/ipilimumab vs chemotherapy: PFS in the population with high TMB (≥10 mut/Mb) and OS in the population with PD-L1 expression ≥1%. The analysis this year at ASCO also included a post hoc analysis of efficacy in patients who discontinued due to TRAEs.

CheckMate 227 Part 1 4-Year Update: Efficacy Outcomes for PD-L1 ≥1% (Part 1a)

Karen L. Reckamp, MD, MS:
Looking at efficacy outcomes in the population of patients with PD-L1 expression ≥1%, we see a 4-year OS rate of nearly 30% with nivolumab/ipilimumab vs 18% for chemotherapy and 21% with nivolumab alone. The OS benefit was seen for both nonsquamous and squamous histology. In patients with nonsquamous disease, the 4-year OS rate was 32%, and in patients with squamous disease, it was a little lower at 20%.26 This update showed that we have a good proportion of patients at 4 years who continue to have extended survival with combination nivolumab/ipilimumab.

CheckMate 227 Part 1 4-Year Update: Efficacy Outcomes for PD-L1 <1% (Part 1b)

Karen L. Reckamp, MD, MS:
Now shifting our attention to patients without PD-L1 expression (ie, the PD-L1 <1% population), we also see evidence of prolonged survival with nivolumab/ipilimumab. The 4-year OS rate with nivolumab/ipilimumab was 24% vs 10% for chemotherapy and 13% with nivolumab alone. Again, the OS benefit with nivolumab/ipilimumab was seen for both nonsquamous and squamous histology, with 4-year OS rates of 25% and 22%, respectively.26 So we see that this immunotherapy combination still shows OS benefit for patients with PD-L1 expression <1%, despite the fact that a formal statistical analysis has not been performed for these arms.

CheckMate 227 Part 1 4-Year Update: Efficacy Outcomes for PD-L1 ≥50%

Karen L. Reckamp, MD, MS:
For patients with PD-L1 expression ≥50%, the 4-year OS rate was 37% in the combination arm—still higher than with chemotherapy at 20% and with nivolumab alone at 26%.26

CheckMate 227 Part 1 4-Year Update: Efficacy in Patients Discontinuing due to TRAEs (Post Hoc Analysis)

Karen L. Reckamp, MD, MS:
In a post hoc analysis, Paz Ares and colleages26 looked at the impact on efficacy of discontinuation of nivolumab/ipilimumab due to TRAEs. In total, 66 patients in the nivolumab/ipilimumab arm with PD-L1 expression ≥1% and 97 with any PD-L1 expression level discontinued because of TRAEs. Of interest, the 4-year OS rate was 44% in both groups, with a median OS of approximately 30 months and 41 months, respectively. This suggests that nivolumab/ipilimumab still can achieve good OS outcomes in a sizeable number of patients despite significant TRAEs.

CheckMate 9LA 2-Year Update: Study Design

Karen L. Reckamp, MD, MS:
We will now shift to a discussion of the 2-year update for the phase III CheckMate 9LA trial comparing nivolumab/ipilimumab plus 2 cycles of chemotherapy vs the standard 4 cycles of chemotherapy as first-line treatment of advanced NSCLC, the study design for which can be seen here.27 The primary endpoint was OS.

CheckMate 9LA Update: Patient Disposition and Subsequent Therapies

Karen L. Reckamp, MD, MS:
Slightly fewer patients went on to receive any therapy in the nivolumab/ipilimumab plus chemotherapy arm (40%) than the chemotherapy arm (47%).27 Many patients went on to receive chemotherapy in both arms (37% vs 24%, respectively). In the nivolumab/ipilimumab plus chemotherapy arm, only 8% went on to receive immunotherapy. In addition, only 37% in the chemotherapy arm went on to receive immunotherapy—even though they hadn’t yet received immunotherapy—which is a little problematic for this cohort of patients.

CheckMate 9LA 2-Year Update: OS in All Randomized Patients

Karen L. Reckamp, MD, MS:
In all randomized patients, the 2-year OS rate was 38% with nivolumab/ipilimumab plus chemotherapy vs 26% with chemotherapy. Median OS was 15.8 months vs 11.0 months, respectively (HR: 0.72; 95% CI: 0.61-0.86).27

CheckMate 9LA Update: OS Subgroup Analysis

Karen L. Reckamp, MD, MS:
As seen in this forest plot, most subgroups analyzed derived an OS benefit from nivolumab/ipilimumab plus chemotherapy.27 Again, we see less OS benefit in patients aged 75 years or older and in patients who have never smoked.

CheckMate 9LA 2-Year Update: PFS

Karen L. Reckamp, MD, MS:
In the nivolumab/ipilimumab plus chemotherapy arm, the 2-year PFS rate was 20% vs 8% with chemotherapy. Median PFS was 6.7 months vs 5.3 months, respectively (HR: 0.67; 95% CI: 0.56-0.79).27

CheckMate 9LA 2-Year Update: Duration of Response

Karen L. Reckamp, MD, MS:
Median duration of response was 13.0 months with nivolumab/ipilimumab plus chemotherapy and 5.6 months with chemotherapy. At 2 years, 34% of patients in the combination arm vs 12% of patients in the chemotherapy arm remained in response.27

CheckMate 9LA 2-Year Update: Safety and Exposure

Karen L. Reckamp, MD, MS:
Looking at safety, rates of any-grade (92% vs 88%) and grade 3/4 (48% vs 38%) TRAEs were slightly higher in the nivolumab/ipilimumab plus chemotherapy arm vs the chemotherapy arm, as were rates of TRAEs leading to discontinuation of any component and serious TRAEs.27

CheckMate 9LA 2-Year Update: Onset of Grade 3/4 TRAEs by Treatment Cycle

Karen L. Reckamp, MD, MS:
The onset of grade 3/4 TRAEs occurred mostly within the first 4 cycles but was seen to persist for many cycles, even to cycle 30.27 For the arm with nivolumab/ipilimumab, this didn’t surprise me, as we know that immune-related AEs can happen at any time. However, I found it intriguing to see that this also happened in the chemotherapy arm.

CheckMate 9LA 2-Year Update: Efficacy in Patients Discontinuing due to TRAEs (Post Hoc Analysis)

Karen L. Reckamp, MD, MS:
Similar to CheckMate 227, as discussed above, Reck and colleagues27 conducted a post hoc analysis of the impact on efficacy of discontinuation due to TRAEs in patients receiving nivolumab/ipilimumab plus chemotherapy. The 2-year OS rate in patients who discontinued all components of the combination regimen due to TRAEs was higher compared with all randomized patients (54% vs 38%, respectively).

CheckMate 227 and CheckMate 9LA: Clinical Implications

Karen L. Reckamp, MD, MS:
There are a lot of data to think about with both the CheckMate 227 4-year update and the CheckMate 9LA 2-year update. In CheckMate 227, there is a clear long-term OS benefit for 15% to 20% of patients receiving nivolumab/ipilimumab, leading to the question of whether we are curing some of these patients. This looks very similar to other immunotherapy trials from which we have seen longer-term updates, with the caveat that we try to avoid cross-trial comparisons. Furthermore, I continue to find it interesting that patients with PD-L1 expression <1% also show prolonged OS with nivolumab/ipilimumab, despite not having statistical significance, and can see a future for this nonchemotherapy regimen in the treatment of our patients with PD-L1–negative disease.

Dr. Piotrowska, what do you think about the CheckMate 227 results?

Zofia Piotrowska, MD, MHS:
I agree. It’s encouraging to see durable, long-term survival outcomes from both of these CheckMate studies, but especially for CheckMate 227 with this 4-year update. There is no doubt in my mind that nivolumab/ipilimumab is an active immunotherapy combination that offers a chemotherapy-sparing approach for patients. However, I do worry about the toxicities associated with this combination, especially the increased risk of immune-related AEs. At the same time, it’s interesting to see that even patients who discontinued due to these toxicities still experienced a striking survival benefit in the long-term. I’ve had some of those patients in my clinic who got just a short duration of treatment and are still doing well. 

However, in my practice, it remains a challenge to know how best to incorporate the CheckMate 227 and CheckMate 9LA data given that the control arm in both studies was chemotherapy alone and that we now primarily use combination chemo-IO in the clinic. I think it’s a chemotherapy-sparing approach for patients who may not be eligible or may not want chemotherapy, although largely, for my patients, I still most commonly recommend combination chemo-IO.

Dr. Reckamp, how do you think about these data in your practice?

Karen L. Reckamp, MD, MS:
I agree. I too have struggled with putting nivolumab/ipilimumab into clinical practice. The increase in immune-related AEs that can sometimes lead to long-term issues for patients has been the biggest barrier for me. But, as I mentioned, I am particularly intrigued by the durable responses and survival outcomes we see with nivolumab/ipilimumab in the patient population with PD-L1 expression <1%, despite this combination not being approved for this indication.

I struggle more with how to integrate the CheckMate 9LA data into my practice. After seeing the 2-year update, the issue with this trial for me, in looking at subsequent therapies, is that only approximately one third of patients who received chemotherapy went on to receive any immunotherapy, and that’s not my population of patients. My patients who receive chemotherapy then progress would go on to immunotherapy. So the OS data are skewed by patients who never received immunotherapy in the chemotherapy arm. Furthermore, the outcomes we see here at the 2-year mark are not significantly better than what we see at the 4-year mark presented for CheckMate 227. So it’s unclear to me what the 2 cycles of chemotherapy with nivolumab/ipilimumab are doing for the patient. Now, seeing these 2 trials juxtaposed at ASCO 2021, I’m not sure that I would expose my patients to 2 cycles of chemotherapy with nivolumab/ipilimumab given the maturing data I see with CheckMate 227.

Zofia Piotrowska, MD, MHS:
I agree. It seems like, if we’re going to give chemo-IO, then the KEYNOTE-189 regimen (ie, pembrolizumab plus chemotherapy) or a similar type of chemo-IO regimen is perfectly adequate. The real potential advantage to giving nivolumab/ipilimumab may be to avoid chemotherapy altogether for patients whom you think can potentially tolerate a higher risk of immune-related AEs. Finally, as you pointed out, the use of the nivolumab/ipilimumab combination may be a way to increase immunotherapy efficacy in PD-L1–negative disease, where single-agent PD-1/PD-L1 inhibitors seem to have less benefit.

Treatment After Progression on Standard-of-Care Immunotherapy Regimens in Advanced NSCLC

Karen L. Reckamp, MD, MS:
To close our discussion on advances in immunotherapy from ASCO 2021, I wanted to briefly mention a few ongoing trials looking at what treatments to offer following progression on immunotherapy. In this space, there are currently 2 main investigational approaches that are most mature: identifying novel inhibitors that may block other pathways or parts of the immune system to overcome resistance to immunotherapy and leveraging combination therapy that includes VEGF inhibition, whether it is anti-VEGF antibodies or small-molecule VEGFR inhibitors such as cabozantinib and lenvatinib.

In the first camp, we saw a trial combining a small-molecule MDM2 inhibitor with pembrolizumab in patients with advanced melanoma and other solid tumors who failed immunotherapy.28 In the second camp, we saw an ongoing phase III trial evaluating cabozantinib, a multikinase inhibitor with activity against VEGFR, in combination with atezolizumab vs docetaxel in metastatic NSCLC pretreated with immunotherapy and chemotherapy.29 This latter category of combining immune checkpoint inhibitors with VEGFR inhibitors is the furthest along in development. Additional new agents that may target other pathways are a bit earlier in development.

Zofia Piotrowska, MD, MHS:
I will add that datopotamab deruxtecan, the TROP2-targeted ADC that we discussed above, is another example of a drug with a novel mechanism of action that I believe will be important in this space. The challenge in the setting of immunotherapy resistance is that later‑line chemotherapy for these patients is not very active, so it will be important to find ways to either reinvigorate the response to immunotherapy or find totally new pathways that we can target.

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