Kim Assesses Multiple Regimens That Demonstrated Efficacy in NSCLC Trials

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In a Targeted Oncology Case-Based Roundtable event Edward S. Kim, MD, MBA, discussed new regimens for the treatment of non-small cell lung cancer.

Edward S. Kim, MD, MBA

Edward S. Kim, MD, MBA

In a Targeted Oncology Case-Based Roundtable event Edward S. Kim, MD, MBA, the physician-in-chief at City of Hope and vice physician-in-chief at City of Hope National Medical Center, discusses new regimens for the treatment of non-small cell lung cancer.

Targeted OncologyTM: What type of molecular testing would you obtain in a patient with nonsquamous non–small cell lung cancer (NSCLC)?

KIM: According to the current National Comprehensive Care Network [NCCN] guidelines [for frontline molecular testing of NSCLC], both liquid and tissue-based, testing absolutely needs to include KRAS, EGFR, ALK, ROS1, BRAF, NTRK1/2/3 fusions, METex 14 skipping variants, and RET; PD-L1 is also something that we try to get up front.1 The [preference] is always to try to get the tissue, to make sure we have a histologic diagnosis, which is something that the blood cannot always give you.

What does the NCCN recommend for patients like this with no driver mutations?

NCCN says that the preferred [category 1] regimen for first line in patients who don’t have these driver mutations and who have PD-L1 expression that ranges from 1% to 49% is a platinum agent [carboplatin or cisplatin] plus pemetrexed [Alimta] and pembrolizumab [Keytruda]. There are other recommended regimens that are also category 1: the regimen of carboplatin, atezolizumab [Tencentriq], bevacizumab [Avastin], and paclitaxel; and nivolumab [Opdivo], ipilimumab [Yervoy], pemetrexed, and a platinum agent. You also have the carboplatin, nab-paclitaxel [Abraxane], and atezolizumab regimen, and included [as “useful in certain circumstances”], the nivolumab plus ipilimumab regimen [category 1], and pembrolizumab [category 2B]. So, there are quite a few options for these adenocarcinomas not otherwise specified.

What is the evidence supporting the use of pembrolizumab with chemotherapy?

KEYNOTE-189 [NCT02578680] was a nice study of chemotherapy—pemetrexed and either carboplatin or cisplatin—plus or minus pembrolizumab. This was for untreated, advanced, metastatic, non-squamous NSCLC, with no driver mutations in EGFR or ALK. It did not require PD-L1 status, though it did [require the collection of] a sample for PD-L1 assessment.2

At the [approximately] 23-month median follow-up, the pembrolizumab combination with chemotherapy was superior from an overall survival [OS] standpoint. At 12 months, the OS rate for the pembrolizumab combination versus placebo was 70.0% versus 48.1%, respectively. At 24 months, the respective rates were 45.5% versus 29.9%. Who knew we were going to get almost 50% survival at 24 months? That’s pretty darn good. Median OS was 22 months [95% CI, 19.5-25.2] versus 10.7 months [95% CI, 8.7-13.6], [HR, 0.56; 95% CI, 0.45-0.70]. Very good, impressive data, and [this] has become the standard of care.3

How did PD-L1 expression influence efficacy?

Regarding PD-L1 expression, there was a real OS benefit for groups with PD-L1 expression that ranged from a TPS of less than 1%, all the way up to greater than 50%. It wasn’t just the [patients with high PD-L1 expression] who had a benefit, so that was reassuring. Among patients whose TPS was less than 1%, median OS was 17.2 months [95% CI, 13.8-22.8] in the pembrolizumab group versus 10.2 months [95% CI, 7.0-13.5] in the placebo group. When TPS ranged from 1% to 49%, median OS was 21.8 months [95% CI, 17.7-25.9] versus 12.1 months [95% CI, 8.7-19.4]. Finally, when TPS exceeded 50%, median OS was not reached [NR] in the pembrolizumab group [95% CI, 20.4-NR] and 10.1 months in the placebo group [95% CI, 7.5-NR].3

What are the data that support other regimens, and for which patient populations?

There is now a whole host of regimens that have joined the KEYNOTE-189 regimen. That doesn’t mean you’re using all of these, clearly, but they were placed on the NCCN guidelines.

[One such regimen is from] KEYNOTE-042 [NCT02220894], looking at metastatic, untreated NSCLC with a TPS of greater than or equal to 1% with no alternation in EGFR or ALK. This was a 1:1 randomization of pembrolizumab at 200 mg, as a single agent, every 3 weeks, versus carboplatin plus paclitaxel or carboplatin plus pemetrexed. This study looked at OS in groups with a TPS of greater than or equal to 50%, 20%, and 1% [to evaluate] the effect of PD-L1.4

When TPS was greater than or equal to 50%, there was a median OS of 20 months [95% CI, 15.4-24.9] versus 12.2 months [95% CI, 10.4-14.2] [HR, 0.69; 95% CI, 0.56-0.85; P = .0003]. When TPS was greater than or equal to 20%, OS was 17.7 months [95% CI, 15.3-22.1] versus 13.0 months [95% CI, 11.6-15.3] [HR, 0.77; 95% CI, 0.64-0.92; P = .0020] and when TPS was greater than or equal to 1%, the OS was 16.7 months [95% CI, 13.9-19.7] versus 12.1 months [95% CI, 11.3-13.3] [HR, 0.81; 95% CI, 0.71-0.93; P = .0018]. In the curves, there’s an early period where the curves cross [and the chemotherapy group shows better OS], but as you get past that 6-month period, [the data] seem to be very much in favor of the single-agent pembrolizumab.5

How did PD-L1 levels correlate with benefit in this study?

When they looked at patients with TPS scores of 1% to 49%, OS was much more similar [between the treatment groups]. Again, the [data showed early benefit in the chemotherapy group, and later benefit in the pembrolizumab group]. Median OS was 13.4 months [95% CI, 10.7-18.2] in the pembrolizumab group versus 12.1 months [95% CI, 11.0-14.0] in the chemotherapy group.4 This was a slight benefit, but certainly not [of] the magnitude that we saw with some of the other cutoffs; it seemed like the higher [PD-L1 levels] were driving the benefit.

What data support the use of atezolizumab and bevacizumab?

The IMpower150 study [NCT02366143] was a unique study, in that it was the only one that had previously allowed patients with sensitizing mutations for EGFR or ALK. It was in chemotherapy-naïve patients with non-squamous NSCLC; patients were tested for PD-L1 status [via immunohistochemical analysis].6,7

This was a 3-arm study. Arm A was atezolizumab with carboplatin and paclitaxel, followed by the atezolizumab maintenance. Arm B was atezolizumab, carboplatin, paclitaxel, and bevacizumab, followed by maintenance with atezolizumab plus bevacizumab. Arm C was carboplatin, paclitaxel, and bevacizumab, followed by bevacizumab maintenance. All these patients were treated with maintenance until the patient had either progression or adverse events [AEs].7

Arm C was the comparator, so Arm A and Arm B were [each] compared with Arm C separately. What they showed was, when you compared Arm B to Arm C, there was benefit in adding the atezolizumab on top of the triplet regimen. The stratified hazard ratio [HR] was 0.78 [95% CI, 0.64-0.96; P = .02].7

There was some crossover [of the curves], but the median OS between these 2 groups was 19.2 months [95% CI, 17.0-23.8] versus 14.7 months [95% CI, 13.3-16.9], so there was something meaningful with the 4-drug regimen.7

Can you talk about data in support of nivolumab and ipilimumab?

The CheckMate 227 trial [NCT02477826] had a patient population with stage IV or recurrent NSCLC; no gene alterations in the tissue were allowed, and both squamous and non-squamous [cancer was included]. Patients were stratified according to PD-L1 expression [greater than or equal to 1% versus less than 1%. These regimens entailed nivolumab and ipilimumab, chemotherapy, or single-agent nivolumab for patients with a PD-L1 level greater than or equal to 1%. Among those with PD-L1 levels less than 1%, the regimens were nivolumab and ipilimumab, chemotherapy, or nivolumab plus chemotherapy.8,9

When they [compared the] nivolumab plus ipilimumab combination with chemotherapy, among patients with a PD-L1 level of greater than or equal to 1%, the HR for OS at the 3-year update was 0.79 [95% CI, 0.67-0.93]. Again, [the curves do] cross at 6 months [at which point the benefit switches from chemotherapy to the nivolumab plus ipilimumab combination].10

When you look at patients with 1% to 49% [PD-L1 expression], there was no difference in median OS [HR, 0.94; 95%CI, 0.75-1.18], as opposed to [other PD-L1 subgroups]. The biggest benefit was among patients with PD-L1 greater than or equal to 50%; median OS was 21.2 months versus 14.0 months [HR, 0.70; 95% CI, 0.55-0.90]. Those middle scores of PD-L1 [didn’t see much benefit].9

Were there concerning AEs with the nivolumab plus ipilimumab combination?

We are always cognizant of AEs. This is what happens when you start going to 4 drugs, or, [as in this case], nivolumab and ipilimumab together. You expect to get some additional AEs when you have nivolumab [plus] ipilimumab. With the dosages that have been utilized, it’s much better tolerated, so it’s a little easier to give. When you look at the grade 3 and grade 4 toxicities, some were worse with nivolumab and ipilimumab, some were worse with chemotherapy. There were more treatment-related AEs [of any grade] leading to discontinuation with the nivolumab and ipilimumab [18.1%] than with chemotherapy [9.1%], and treatment-related AEs of grade 3 or 4 [that led to discontinuation] were 12.3% versus 4.9%, respectively, so those are things that we keep in mind.9

What other data shed light on nivolumab plus ipilimumab?

CheckMate 9LA [NCT03215706] was a study of advanced or recurrent NSCLC with no prior systemic therapy, no genomic alterations, and a good ECOG performance status, stratified by PD-L1 [expression] less than 1% versus greater than or equal to 1% and histology [squamous versus non-squamous]. [The treatment arm was] nivolumab, ipilimumab, and chemotherapy—2 cycles of chemotherapy, not concurrent; the control arm was chemotherapy for 4 cycles, and pemetrexed maintenance could be given to non-squamous patients. OS was the primary end point.11,12

There was a benefit in OS [for patients who received nivolumab and ipilimumab with chemotherapy, versus chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80)].12 Median OS was 15.6 months [95% CI, 13.9-20.0] versus 10.9 months [95% CI, 9.5-12.6], respectively, and response rate was 38% versus 25%, showing some benefit, again, in OS in the upfront setting.

[They also took] a more detailed look at [OS and] PD-L1 expression. When PD-L1 expression was less than 1%, the HR was 0.62 [95% CI, 0.45-0.85]. When PD-L1 expression was greater than or equal to 1%, the HR was 0.64 [95% CI, 0.50-0.82]. [When expression was] greater than or equal to 50%, the HR was 0.66 [95% CI, 0.44-0.99]. [Finally], in the intermediate [range of PD-L1 expression], (1% to 49%), there was still a benefit, with a HR of 0.61 [95% CI, 0.44-0.84].11

Chemotherapy had more treatment-related AEs than did the nivolumab and ipilimumab plus chemotherapy. [These results] show that you can disperse some of the AEs by not stacking the drugs on top of each other, and [instead] giving them in a sequential manner. I thought this was a clever trial from that standpoint. Now we have approvals for both of these regimens, [the nivolumab plus ipilimumab regimen,13 and nivolumab, ipilimumab, plus chemotherapy regimen].14

What are the data describing the efficacy and side effects of docetaxel (Taxotere) and ramucirumab (Cyramza)?

REVEL [NCT01168973] was [a study of docetaxel with either ramucirumab or with placebo]. [According to the design, patients had had] 1 platinum-based chemotherapy; prior bevacizumab was allowed, as were both [squamous and non-squamous] histologies.15 Ramucirumab is a VEGF-targeted drug; [it is] a little different than bevacizumab, and the study did allow prior [treatment with] bevacizumab. They did have some of the traditional VEGF exclusion criteria in this study, because there was a little bit of fear in that, but again, it’s a different drug than bevacizumab, so people were treated [until] progression.

[This study takes us back] to when we didn’t have a lot of biologic driver mutation data or subsets. Median OS was slightly better with ramucirumab, 10.5 months versus 9.1 months [HR, 0.86; 95% CI, 0.75-0.98; P = .02]. Progression-free survival improved from 3.0 months to 4.5 months [HR, 0.76; 95% CI, 0.68-0.86; P < .0001]. The objective response rate was probably the most robust [data point], 23% versus 14% [odds ratio, 1.89; 95% CI, 1.41-2.54; P < .0001].15

There was an exploratory [analysis]. They defined refractory [in terms of] the best response of progressive disease to first-line therapy, so these were patients who did not get stable disease or any type of response, and then progression. There were 360 patients like that.16 [The investigators] wanted to see if, indeed, being aggressive with this combination was helpful.

The efficacy breakdown was purely a post hoc analysis. The median OS was in favor of ramucirumab plus docetaxel, and whether duration of the first-line therapy was 4, 8, or 12 weeks, there was a benefit across the board; for example, HR at 12 weeks was 0.85 [95% CI, 0.68-1.05]. What it speaks to is that, if you see someone who’s in trouble, especially who’s having progression like this, maybe it’s okay to be a little more aggressive. I think finding a clinical trial would be nice, especially in patients who are refractory to immunotherapy, especially when they progress quickly.

We do know that there are some AEs. Treatment-emergent AEs of grade 3 or higher were more common in the ramucirumab group [79% vs 71%],15 as well as treatment-emergent AEs that were related to discontinuation [5% vs 4%], there were definitely higher numbers with the ramucirumab and docetaxel. 16 Docetaxel by itself is not a benign regimen; it does have AEs.

1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2021. Accessed June 28, 2021.
2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
3. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non–small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136
4. Mok TSK, Wu YL, Kudaba I, et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7
5. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(suppl 18). doi:10.1200/JCO.2018.36.18_suppl.LBA4
6. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002
7. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948
8. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
9. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
10. 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
11. Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501
12. Paz-Ares L, Ciuleanu T-E, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncology. 2021;22(2):198-211. Published correction appears in Lancet Oncology. 2021;22(3):e92. doi:10.1016/S1470-2045(20)30641-0
13. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. Published May 15, 2020. Accessed July 8, 2021.
14. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. News release. US Food and Drug Administration. Updated May 27, 2020. Accessed June 29, 2021.
15. 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, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X
16. 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
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