Four-Drug Atezolizumab Regimen Impacts Outcomes in Bulky NSCLC

Robert Jotte, MD, PhD

Bevacizumab (Avastin) in combination with carboplatin and paclitaxel (BCP) has historically improved survival in patients with non–small cell lung cancer (NSCLC) who had no prior chemotherapy for metastatic nonsquamous disease. An idea to explore outcomes in these patients when atezolizumab (Tecentriq) was added to BCP was fostered based on the knowledge that this patient population traditionally had poor outcomes and requires novel treatment options.

In an exploratory analysis, investigators assessed patients from the phase 3 Impower150 study (NCT02366143), which, according to recent data presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit in patients with NSCLC and bulky disease who were randomize to received either ABCP, atezolizumab plus carboplatin and paclitaxel (ACP), or BCP.

The results showed that ORR was the only outcome that favored patients with high tumor burden over low tumor burden. The overall response rate among patients with high tumor burden was 62% in the ABCP arm and 41% in the BCP arm. For patients with low tumor burden, the ORR was 53% versus 40%, respectively. The time to response (TTR) was 1.5 months with ABCP versus 1.6 months with BCP in the high tumor burden group and 1.8 months with ABCP versus 1.5 months with BCP in the low tumor burden group. Overall, TTR was not impacted by tumor burden.

A higher median OS in the ABCP and BCP arms were observed in patients with low tumor burden, where the hazard ratio was 0.83 (95% CI, 0.68-1.02) compared with 0.70 (95% CI, 0.5-0.97). The median OS results in the low tumor burden population were 20.3 months with ABCP and 17.1 months for BCP. In patients with high tumor burden, the median OS was 15.5 months with ABCP compared with 10.7 months with the BCP regimen.

PFS was also better for patients with low tumor burden. The median PFS in the low tumor burden population was 9.6 months in the ABCP group versus 7.1 months in the BCP group (HR, 0.59; 95% CI, 0.49-0.71). In the high tumor burden population, the median PFS was 7.3 months for the ABCP arm compared with 5.8 months for the BCP arm (HR, 0.52; 95% CI, 0.37-072).

The ABCP arm also demonstrated a comparable safety profile in patients with bulky disease and wild-type disease in the intention-to-treat (ITT) population.

In an interview with Targeted Oncology, Robert M. Jotte, MD, PhD, medical oncologist, and hematologist, Rocky Mountain Cancer Centers, discussed the results of the exploratory analysis of patients with NSCLC from the IMpower150 who had bulky disease.

TARGETED ONCOLOGY: Can you recap the overall results from the IMpower150 study?

Jotte: The IMpower150 [study] was a phase 3 trial that was conducted internationally at multiple centers that randomized just over 1200 patients into 3 arms, and it was open label. These were patients that had never experienced any treatment before. Chemotherapy-naïve patients that had nonsquamous metastatic NSCLC. Patients were randomized in a 1:1:1 ratio to either receive ABCP or ACP. The primary end points that we were looking at were investigator-assessed PFS, as well as OS in the intent-to-treat population. These were all wild-type patients, meaning the patients did not harbor EGFR or ALK genomic alterations.

What we saw in those results is that the median PFS in arm B, which is the ABCP arm, was 8.3 months versus the comparator control arm (arm C), which was 6.8 months and that was with a hazard ratio of 0.62 and a P value of less than .0001. The OS results demonstrated a survival benefit in favor of arm B over arm C with a hazard ratio of 0.8 and a median survival of 19.5 months versus 14.7 months. The boundary for statistical significance for OS in arm A has not yet been reached, which is why we don't have that comparison, at least at this point in time.

TARGETED ONCOLOGY: How do survival outcomes differ between patients with bulky disease and those with other nonsquamous NSCLC?

Jotte: We know that patients with bulky disease tend to have a higher disease burden, and they're typically considered to have more aggressive NSCLC. We know that aggressive disease behavior typically results in poor clinical outcomes. Those patients might not respond to first-line therapy or later-line therapy. Therefore, we're struggling more with controlling their disease. They have a more rapid time to progression and therefore, shorter survival. This was shown in other things we’ve investigated, in terms of brain metastases or liver metastases. Bulky disease falls in alignment with those same things.

TARGETED ONCOLOGY: What was the rationale for conducting the exploratory analysis on patients with bulky disease?

Jotte: Again, we know that these patients tend to have poor outcomes. When we initially conducted the IMpower150 study, we saw that patients that had metastatic liver disease tended to do better in the 4-arm regimen, arm B. “Aggressive” is a broad term that we use to describe tumors that develop, progress, and metastasize more quickly than those that don't fall under that definition. We use this term “aggressive” to try and identify subsets of patients that have a more unfavorable clinical course compared to those that might not fall into that category, and therefore might derive different benefits and hopefully better benefits from specific therapeutic approaches. In this case, the therapeutic approach was ABCP.

We did this exploratory analysis specifically to look at this patient population in order to see if they derived a greater benefit from that 4-drug or quad regimen.

TARGETED ONCOLOGY: What were the findings presented at ASCO 2020?

Jotte: We found that certain patients fell into the category of [deriving benefit from the ABCP therapy]. The higher disease burden did have poor OS, PFS, and TTR in both arms compared to patients with lower disease burden, despite or regardless of whichever treatment they use, and regardless of the approach to use to define what bulky is, that's pretty consistent with what we would expect to see in these patients that have poor survival outcomes. But we did see treatment effect observed across the key efficacy outcomes. That’s the OS finding.

But, the addition of atezolizumab to bevacizumab, carboplatin, and paclitaxel did have a greater treatment effect in terms of the OS and PFS in patients with high disease burden than it did in patients with lower disease burdens. The ORR benefit when atezolizumab was added to the 3-drug regimen was more pronounced in higher versus low disease burden, with no impact from disease burden on TTR for either treatment arm.

Importantly, the toxicity profile in patients with high tumor burden was consistent with a known profile of this 4-drug regimen and the intent-to-treat population with no new safety signals observed for this subgroup. That’s important to have. Even despite this heavy tumor burden patient population having poorer expected outcomes, all patients experienced similar toxicities.

TARGETED ONCOLOGY: What conclusions were drawn about ABCP from these findings?

Jotte: In a subgroup analysis, we did demonstrate the clinical benefit of ABCP, and paclitaxel, over the ACP regimen in patients regardless of their disease burden. That stands whether you define them in terms of when we evaluate these patients or the median number of metastatic sites.

Despite their tumor burden versus the number of metastatic sites, we saw clinical benefit across those different groups. These data really highlight the efficacy of this 4-drug combination in patients that do have bulky disease, and once again, underscores the need for an active regimen for the subgroup of patients with aggressive disease who, again, historically have always carried a poorer prognosis than their counterparts.

_Reference:

_{Jotte RM, Batus M, Bernicker E et al. IMpower150: Exploratory efficacy analysis in patients (pts) with bulky disease. J Clin Oncol. 2020;38(suppl):e21637. doi:10.1200/JCO.2020.38.15_suppl.e21637}