In Patients With NSCLC Relapsing Shortly After Frontline Therapy Initiation, Ramucirumab Combination Impresses

Antoinette Wozniak, MD

During a Targeted Oncology Case Based Peer Perspectives event, Antoinette Wozniak, MD, professor of Medicine, associate director of Clinical Research, director, Lung Cancer Disease Unit, codirector, University of Pittsburgh, Medical Center (UPMC) Lung Cancer Center of Excellence, UPMC Hillman Cancer Center, discussed the case of a 59-year-old man with non-small cell lung cancer (NSCLC).

Targeted Oncology™: What kind of biomarker testing would you perform for this patient?

WOZNIAK: I know a lot of oncologists who do both tumor and liquid biopsy because you might get the liquid biopsy back faster. I have done that. Usually up front, I like to use tissue. We used [to] get the Oncomine Dx Target Test because we get a lot of information with a small amount of tissue.1 We use liquid biopsies if I don’t have enough tissue.

I think the cost of next-generation sequencing [NGS] has come down quite a bit. The good thing about it is that you do get a lot of information from a little bit of tissue. If you do 1 test at a time in a sequential fashion, which is what we used to do, it takes too much tissue, so it’s nice to have NGS. I think if given the option of liquid versus regular tissue biopsy, I would do the regular tissue biopsy because you might miss some things. If you have patients who don’t shed tumor cells into their circulation, you might have difficulty getting enough information from your liquid biopsy. I think NGS out in the community [can be performed] with a number of companies. Caris [Life Sciences] is one of them as well as Foundation Medicine. If I remember correctly from my old institution, a lot of these places would do the sequencing and bill insurance but not the patients. They’ve been pretty good about it, and I think in a community setting you can do these things.

Are there any recent FDA approvals that would influence what you might do for this patient?

In particular, there’s a specific RET inhibitor that’s approved, selpercatinib [Retevmo],² as well as capmatinib [Tabrecta], which is a MET inhibitor.³ There are things that are happening that will direct your treatment.

What molecular testing should be performed here?

The NCCN [National Comprehensive Cancer Network] recommends that at minimum you should test for EGFR, ALK, ROS1, BRAF, MET exon 14, RET, and PD-L1.⁴ They recommend NGS, mainly because it minimizes tissue use. You can also pick up some of the rarer mutations, like an NTRK. I’ve never seen one, but apparently they do occur. The PD-L1 assay that they suggest is the Dako 22C3 [PD-L1 IHC 22C3 pharmDx] assay.⁵

If you do have insufficient tissue to allow all of this testing to occur, or if there’s some other circumstance, then plasma testing should be done. If you still don’t have your answer—either because the plasma testing didn’t show you anything, because you didn’t have enough tissue to do other testing, or you couldn’t do another biopsy—then you treat patients as if they did not have a driver mutation.

What would be your preferred recommendation for this patient?

The preferred treatment would be carboplatin or cisplatin with pemetrexed [Alimta] and pembrolizumab [Keytruda]. It has a category 1 recommendation by the NCCN guidelines.⁴

Other recommendations are [also] valid treatments, if you choose them.

Which data support the use of pembrolizumab plus chemotherapy in this type of patient?

KEYNOTE-189 [NCT02578680] was an important trial. The patients had nonsquamous, metastatic, frontline disease. Patients were randomized to chemotherapy with carboplatin or cisplatin with pemetrexed and pembrolizumab chemotherapy plus placebo. This was a blinded trial. They collected data on PD-L1 status, but they did not require that patients have PD-L1–positive tumors. There were coprimary end points of overall survival [OS] and progression-free survival [PFS].⁶

An update of these survival data on KEYNOTE-189 shows improvement in survival for pembrolizumab, with a hazard ratio [of] 0.56 [95% CI, 0.45-0.70]. At 24 months, 45.5% of the patients were alive versus 29.9% with chemotherapy alone. I remember when we were happy to have 50% of patients surviving at 12 months with 1 of the trials involving bevacizumab [Avastin]. This was a tremendous improvement. The median survival was over double with pembrolizumab versus chemotherapy alone [22.0 months vs 10.7 months]. Now, we’re not supposed to do trial-to-trial comparisons, but we’re human. It certainly gives us an idea of how the other trials fared with the survival results.⁷

Breaking it down by PD-L1 expression status, the OS in every category—even when the TPS [tumor proportion score] was less than 1%—[showed] a significant improvement in survival. Up until these last few years, we never saw this kind of survival for patients with advanced lung cancer, so this was exciting.

The patients with a higher TPS score had a better PFS, but all groups had significant outcomes. The benefit was seen in all these groups. The response rate was also better for the chemotherapy plus pembrolizumab arm. The duration of response was excellent as well.

Would you consider using single-agent pembrolizumab for this patient?

This is KEYNOTE-042, which was presented in a plenary presentation at the American Society of Clinical Oncology [ASCO] annual meeting a couple of years ago.8 In this trial, patients had to have a TPS score of 1% or better and they were randomized to pembrolizumab alone or chemotherapy. The chemotherapy choice was histology driven. Nearly half the patients had a high TPS score [≥ 50%].

At various PD-L1 cutoffs, there was a difference in the median PFS. As you include patients who had lower PD-L1 status, the [Kaplan-Meier] curves come together and the hazard ratios change. For the OS, the hazard ratios do come down as you consider lower TPS score patients.

In the group of 1% or greater PD-L1 expression, up to 49%, there was no statistical significance in the OS difference between therapies [HR, 1.07; 95% CI, 0.94-1.21]. The survival was really driven by patients with a high TPS score of 50% or better; that’s who drove the survival improvement in this study. Yet because of this study, pembrolizumab is approved as a single agent for patients with a TPS score of 1% or better.9 That’s because it may not be better than chemotherapy, but it’s at least as good as chemotherapy. However, I’m not sure it’s as good as pembrolizumab plus chemotherapy. I think it’s a reasonable thing [to consider] in someone maybe who refuses chemotherapy.

Are there other PD-L1 inhibitors that are approved for this setting?

The IMpower150 trial [NCT02366143] included patients who were randomized to 3 different treatments. Arm A was atezolizumab [Tecentriq] and chemotherapy of carboplatin/paclitaxel. Arm C was carboplatin, paclitaxel, and bevacizumab [Avastin]. Many of us were using that regimen prior to immunotherapy. This is one of the few trials that included patients who were EGFR- or ALK mutation positive and had failed on their treatments with TKIs [tyrosine kinase inhibitors]. All the other immunotherapy trials did not include them.

The comparison of arm B—which was all 4 drugs—versus carboplatin, paclitaxel, and bevacizumab was published in the New England Journal of Medicine.¹⁰ With the addition of atezolizumab to bevacizumab and chemotherapy, there was a significant improvement in survival [HR, 0.78; 95% CI, 0.64-0.96; P = .02]. At 24 months, the survival rate was 43.3% for the atezolizumab arm versus 33.7% for the control arm.

They also compared arm C to arm A; that was chemotherapy plus atezolizumab versus chemotherapy plus bevacizumab. The chemotherapy/atezolizumab arm was a little better, but so far there’s only a trend toward an OS benefit. Many of us wanted them to compare arm A to arm B, but that didn’t happen. That would compare the arm that had immunotherapy in both arms, but bevacizumab in 1 of the arms. Unfortunately, that wasn’t part of their analysis.

There is another study, IMpower130 [NCT02367781], which included patients with nonsquamous non–small cell lung cancer.¹¹ They were randomized to atezolizumab plus carboplatin and nab-paclitaxel [Abraxane] versus chemotherapy alone.

The PFS and the OS both favored the atezolizumab-containing arm. The 2-year survival rate was close to 40% with atezolizumab versus 30% with chemotherapy. That is a little less than what we’ve seen on the other studies; but again, we’re comparing a trial to another trial and there could be differences in the patient populations.

Which data support options for combination immunotherapy in a patient such as this?

The CheckMate 227 trial [NCT02477826] looked at nivolumab [Opdivo] plus ipilimumab [Yervoy] versus [the] chemotherapy arm.¹² You have 2 groups of patients. You have those who had 1% or greater [and those with less than 1%] PD-L1 expression. They compared nivolumab/ipilimumab versus histology-based chemotherapy. This included squamous histology; about 25% of patients had squamous histology on this trial.

In patients with a 1% or greater PD-L1 expression, there was a significant improvement in survival…. The hazard ratio was 0.79 [97.72% CI, 0.65-0.96]. This combination was approved by the FDA in May for treatment of patients with a PD-L1 expression level of 1% of greater.¹³

There was another group of patients in CheckMate 227. Those were the ones that had close to a negative PD-L1 status. The investigators did an analysis looking at different subgroups. If you look at the subgroups, the interesting thing is that even in the patients who had a PD-L1 expression of less than 1%, they seem to have survival benefit based on the forest plot [HR, 0.62; 95% CI, 0.49-0.79]. They did some additional exploratory subgroup analysis, but I think that’s the more interesting part of this.

Now, the FDA indication is only for patients with PD-L1 expression status of 1% or [greater] because this group of patients was not part of the primary analysis. The combination isn’t approved for this group of patients, but this is an interesting part of these data.

At this past ASCO annual meeting, they [showed data that] broke down PFS by PD-L1 status, and you can see this in the PFS. Out 36 months, 18% [of patients given ipililumab] and 4% [given chemotherapy] of those with PD-L1 status of less than 1% were progression free versus 13% and 2%, respectively, [of those with 1% or greater PD-L1 expression]. In both groups of patients, you do see some benefit for the combination.¹⁴

AEs [adverse events with nivolumab/ipilimumab] are what you would expect for immunotherapy. In terms of treatmentrelated serious AEs that led to a discontinuation of treatment, that was a little higher for the nivolumab/ipilimumab arm versus chemotherapy.

Most of the immune-related events occurred within the first 6 months of treatment. We do see them after 6 months, but to a lesser degree. They’re what you would expect: skin toxicity, gastrointestinal toxicity, and pulmonary toxicity, among others. Another study, the CheckMate 9LA study [NCT03215706], was presented in an oral session at the ASCO annual meeting 2020.…They examined nivolumab/ipilimumab, but in the experimental arm they added 2 cycles of chemotherapy up front. Nivolumab was given every 3 weeks at 360 mg. They compared the experimental regimen to chemotherapy.

I listened to this presentation again, and they don’t say why they did this, but I think they did this because they felt that maybe nivolumab/ipilimumab, just the immunotherapy by itself, might not be enough for some patients. It takes a little time for the immunotherapy to work. By adding the chemotherapy, you get more bang for your buck right up front, so [maybe] that’s why this was done.

When you look at this trial, the primary end point was OS. You can see that by the addition of a couple of courses of chemotherapy, there was an improvement in the OS. The results are early still, but the hazard ratio looks pretty good at 0.66 [95% CI, 0.55-0.80]. They did look at OS by PD-L1 expression, whether it’s less than 1%, greater than or equal to 1%, 1% to 49%, or 50% or more. There was benefit for all these groups with similar hazard ratios and similar [Kaplan-Meier] curves. The response rate was better with the addition of some chemotherapy and the PFS also was better.

The AEs typically associated with chemotherapy are about the same [as the immunotherapy combination], but sometimes a little bit more toward the chemotherapy-alone portion. Then, below that, you’ll see the toxicities associated with immunotherapy are as would be expected. The majority of them are early grade 1/2 effects.

Just recently, the FDA did approve the combination of nivolumab/ipilimumab with the 2 cycles of chemotherapy for treatment in first-line metastatic NSCLC.¹⁵

What is the rationale behind this choice of therapy?

This treatment is based on the REVEL trial [NCT01168973].¹⁶ Docetaxel made a comeback because after immunotherapy there isn’t a lot available [for patients] except if they’re eligible for a clinical trial. This trial included all histologies—even squamous, despite the fact that ramucirumab is a VEGF inhibitor. However, they had very specific exclusion criteria. Patients couldn’t have any major involvement of their blood vessels; no cavitation, which can lead to, obviously, hemoptysis; no recent thromboembolic event; and they couldn’t have any gross hemoptysis. They were specific patients who were less likely to bleed. Patients were randomized to get ramucirumab and docetaxel or docetaxel alone. Of course, the standard-of-care dose is 75 mg/m², which I find to be difficult to give my patients at times.

Patients with squamous histology made up about 25% [of the population]. A small number of tumors were EGFR mutation, and some [patients] also had previous taxanes, usually nab-paclitaxel or paclitaxel. In the early trials with docetaxel, when it was initially approved, it was the first drug approved in the second line for NSCLC. One of the large trials allowed prior paclitaxel, and it didn’t make a difference whether patients had prior taxanes, so that’s why that’s there.

This [Kaplan-Meier curve for survival] is not as spectacular as the others, but there were a lot of patients on this trial, over 600 on each arm. The median OS was modest, 10.5 months versus 9.1 months [HR, 0.86; P = .02], as is the median PFS [4.5 months vs. 3.0 months; HR, 0.75; P < .0001]. Even though this is statistically significant, the separation of the curves is modest.

They didn’t do a lot of subgroup analyses, but one thing they did look at was patients who were fairly refractory. They looked at patients who were on first-line therapy for at least 4, 8, and 12 weeks.¹⁷

Patients seemed to do better when they were more refractory at the outset with their first-line therapy, particularly in that less-than-or-equal-to-4-week category. The hazard ratio and the median OS were better by over 5 months [8.8 months with ramucirumab vs. 3.2 with docetaxel alone; HR, 0.40].

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_{11. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):924-937. doi:10.1016/S1470-2045(19)30167-6}

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_{13. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥ 1%). FDA. May 15, 2020. Accessed October 15, 2020. https://bit.ly/3j3XdCk}

_{14. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 part 1. J Clin Oncol. 2020;38 (suppl 15):9500. doi:10.1200/JCO.2020.38.15_suppl.9500}

_{15. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. Updated May 27, 2020. Accessed October 15, 2020. https://bit.ly/2T2DxEm}

_{16. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, doubleblind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X}

_{17. Reck M, Paz-Ares L, Bidoli P, et al. Outcomes in patients with aggressive or refractory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181-187. doi:10.1016/j.lungcan.2017.07.038}