Will Combination Therapies With Immunotherapy Become the New Standard of Care For NSCLC?

Naiyer A. Rizvi, MD

Naiyer A. Rizvi, MD

After the accelerated FDA approval of pembrolizumab (Keytruda) for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous non—small cell lung cancer (NSCLC), rapid growth continues for research surrounding combination therapies of immunotherapy with chemotherapy for patients with NSCLC.

Cohort G of the KEYNOTE-021 trial, which led to the frontline combination approval, evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy (carboplatin and pemetrexed) versus chemotherapy alone as first-line therapy for patients with advanced NSCLC. The study demonstrated significant improvements in profession-free survival (PFS) with pembrolizumab plus chemotherapy with a median PFS of 19.0 months versus 8.9 months with chemotherapy alone (HR, 0.54; 95% CI, 0.33-0.88,P= .0067). Additionally, the overall response rate was 57% with pembrolizumab and 32% with chemotherapy alone (estimated difference, 25%; 95% CI, 7%-41%;P= .0029).¹

While some mark the combination therapy approval as a milestone in the treatment of lung cancer, others continue to favor pembrolizumab monotherapy as the preferable frontline for patients with NSCLC, which was approved for patients with high PD-L1 expression. At the2nd AnnualInternational Congress on Immunotherapies in Cancerhosted by Physicians’ Education Resource, LLC, Naiyer A. Rizvi, MD, touched upon these reservations while also expressing hope for the future of combination therapy for NSCLC with recent findings from the IMPower150 trial.

A chain reaction from KEYNOTE-021G, the phase III IMpower150 trial evaluated the efficacy and safety of atezolizumab (Tecentriq) in combination with chemotherapy (carboplatin and paclitaxel) with or without bevacizumab (Avastin) in chemotherapy-naïve patients with NSCLC.²Atezolizumab is 1 of 3 immunotherapy drugs in the United States approved as a monotherapy treatment for patients with metastatic NSCLC following progression on chemotherapy in the second-line setting or beyond.

“I think that [atezolizumab with chemotherapy] is a new treatment option for frontline patients with NSCLC. [IMpower150] was a positive trial [and] met its primary endpoint,” said Rizvi, director of thoracic oncology and co-director of the Cancer Immunotherapy Program at Columbia University Medical Center, during his presentation.

In the study, 1202 patients were randomized 1:1:1 to 1 of 3 arms: chemotherapy plus atezolizumab (arm A), chemotherapy plus atezolizumab and bevacizumab (arm B), or chemotherapy plus bevacizumab (arm C, control arm). Those with knownEGFRorALKalterations were excluded from the primary intention-to-treat analysis. Additionally, patients were also tested for a tumor T-effector gene expression signature which included expression of PD-L1, CXCL9, and interferon-gamma.

Those in the investigational arms received atezolizumab administered intravenously at 1200 mg every 3 weeks and bevacizumab at 15 mg/kg. Carboplatin and paclitaxel were administered on day 1 of each cycle for 4 to 6 cycles for all arms. Following the induction phase, patients in arm A received maintenance treatment with atezolizumab alone, while those in arm B received a combination of atezolizumab and bevacizumab. In the control arm, patients were treated with maintenance bevacizumab alone.

The study’s co-primary endpoints were PFS and overall survival (OS). During the presentation, Rizvi noted that the trial’s preliminary examination of OS showed that it did not meet this endpoint in terms of significance, but that “…this was a relatively early snapshot and, as is the case with [immunotherapy] in general, if you follow them out further, you are likely to see further separation with OS.” Further OS analysis will take place in the first half of 2018.

In terms of PFS, IMpower150 was positive and met its endpoint per study protocol for both arm A and arm B. The atezolizumab regimen demonstrated a median PFS of 8.3 months compared with 6.8 months with bevacizumab and chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.74;P<.0001). Additionally, the 12-month PFS rate was 37% with the atezolizumab regimen and 18% with the bevacizumab plus chemotherapy regimen.

Although the data from IMpower150 look convincing, Rizvi considered the lack of correlation between the trial and the former KEYNOTE-021G trial. &ldquo;It doesn&rsquo;t seem like the data from [KEYNOTE-021G] are being recapitulated in IMPower150. Is this because the pembrolizumab combinations are better, is there something unique to 21G, or is it simply that it is a smaller study and subject to more variability?&rdquo; While the pembrolizumab combination had a PFS of 19 months, the atezolizumab combination reached only 6.8 months.

While Rizvi continues to lean in favor of pembrolizumab monotherapy for PD-L1—positive patients, he acknowledges that he would consider the chemotherapy combination for specific biomarker subgroups. &ldquo;I think we are just scratching the surface of using RNA signatures to identify patients for these therapies, as discussed [in] renal cell cancer. There are patterns of RNA signatures based not only on T-effector, but also myeloid inflammation.&rdquo;

The IMmotion150 phase II trial evaluated the efficacy of the atezolizumab and bevacizumab combination versus sunitinib (Sutent) in patients with PD-L1—positive advanced or metastatic renal cell carcinoma (mRCC). In the positive trial, the combination was associated with a statistically significant reduction in the risk for death or progression by 36% compared to sunitinib (HR, 0.64; 95% CI, 0.38-1.08;P<.0001).³

An exploratory endpoint in the IMmotion150 study examined the association between outcome and tumor microenvironment gene signatures. A small group of patients were divided into 3 subgroups: angiogenesis, T-effector signature, or myeloid inflammation.

For patients who were T-effector—high and myeloid-low, atezolizumab alone or with bevacizumab showed better efficacy compared with sunitinib. However, patients who were T-effector high, myeloid-high had better outcomes with the combination rather than with atezolizumab monotherapy. This suggests that the addition of bevacizumab enhanced the immune responsiveness of atezolizumab.

&ldquo;These 2 signatures potentially could be better and are going to need to be looked at in the IMpower150 lung cancer trial,&rdquo; suggested Rizvi. &ldquo;As this data is analyzed further, we may be able to find subsets that may be more appropriate for adding bevacizumab to treatment.&rdquo;

In the IMpower150 trial, patients with a T-effector—high signature had a significantly improved PFS of 11.3 months with the addition of atezolizumab, versus 6.8 months with bevacizumab plus chemotherapy alone (HR, 0.51; 95% CI: 0.38-0.68;P<.0001). Although both hazard ratios were positive, the patients with PD-L1 expression still showed greater significance.

Rizvi further mentioned the data surrounding theEGFR-andALK-positive patients was &ldquo;pretty impressive.&rdquo; The IMpower150 study showed a median PFS of 9.7 months forEGFR-andALK-positive patients (n = 108) receiving atezolizumab plus bevacizumab and chemotherapy versus only 6.1 months for those receiving bevacizumab and chemotherapy alone.

This may shed new hope for such patients who normally do not respond well to immunotherapy. &ldquo;In terms of clinical practice, if I have a patient who progresses on TKI and needs to go on chemotherapy, this is a regimen that I would seriously consider. To argue for chemotherapy, there are going to be subsets where it is definitely worth considering this combination,&rdquo; he said.

Additionally, patients (n = 94) with known liver metastases responded better to combination therapy than to immunotherapy alone. The median PFS for patients in arm A was 7.4 months compared to only 4.9 months in arm C (HR, 0.42). Rizvi mentioned, &ldquo;the response rates, if you have liver [metastases], are half that if you do not,&rdquo; again suggesting, &ldquo;there are certain subgroups, such asEGFR/ALKmutants and liver metastases, where I think that this IMPower150 strategy is a good one."

With a surge in combination therapy trials and approvals, a new standard of care may result for patients with NSCLC. &ldquo;These data do look compelling&hellip;. One can&rsquo;t argue with these survival curves. There seems to be something to the KEYNOTE-21G story,&rdquo; Rizvi said. Still, he continues to favor pembrolizumab monotherapy for patients with PD-L1—positive NSCLC.

Nonetheless, he remains hopeful that chemotherapy combinations will find their place in the frontline setting as &ldquo;&hellip;we look as RNA signatures.&rdquo; He admits that there are &ldquo;&hellip;. certain subsets where this regimen would be better,&rdquo; includingEGFR/ALKrearrangements and liver metastases.

Joining IMpower150, several studies continue to assess atezolizumab as part of various combinations for the treatment of patients with lung cancer. Additionally, the combination of atezolizumab and bevacizumab is being assess in several other solid tumors, with promising findings presented in renal cell carcinoma. Trials looking at this combination are currently ongoing.

References

1. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.Lancet Oncol. 016;17(11):1497-1508.
2. Reck M. Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/&minus; bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Annals of Oncology, 2017;28(11). Abstract LBA1_PR.
3. Powles T, McDermotee SF, Rini B, et al. IMmotion150: Novel radiological endpoints and updated data from a randomized phase II trial investigating atezolizumab (atezo) with or without bevacizumab (bev) vs sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA39.