Immunotherapy Takes Hold in Frontline Advanced Nonsquamous NSCLC

Jyoti D. Patel, MD, FASCO

Frontline immunotherapy has shown tremendous benefit in patients with advanced nonsquamous non—small cell lung cancer (NSCLC), but it should only be given in the absence of a driver mutation, according to Jyoti D. Patel, MD, FASCO.

“We need to determine up front whether there is a genotypic driver present, so we know whether to proceed with targeted therapy versus immunotherapy,” said Patel, a professor of medicine and director of Thoracic Oncology at the University of Chicago Medicine. “If you have to treat immediately because of disease burden or progressive symptoms, I would recommend giving chemotherapy alone. If the patient doesn’t have a driver, you can add in immunotherapy at that juncture.”

Both pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are approved for use in combination with platinum-based chemotherapy in this setting and have demonstrated encouraging data in phase III trials. In updated data from the phase III KEYNOTE-189 study, which was the confirmatory trial for the pembrolizumab/chemotherapy approval, the addition of pembrolizumab to carboplatin and pemetrexed resulted in a 44% reduction in the risk of death versus chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70;&#8239; P&#8239; <.00001).¹

Secondly, in the phase III IMpower150 trial, the addition of atezolizumab to carboplatin, paclitaxel, and bevacizumab (Avastin) reduced the risk of death by 22% versus chemotherapy/bevacizumab alone (HR, 0.78; 95% CI, 0.64-0.96;&#8239; P &#8239;=.02).²

Notably, pembrolizumab is also approved for use as monotherapy in patients with a PD-L1 tumor proportion score (TPS) ≥1%, after demonstrating favorable overall survival (OS) benefit versus chemotherapy in the phase III KEYNOTE-042 trial (HR, 0.81; 95% CI, 0.71-0.93;&#8239; P &#8239;= .0018).³ Notably, higher PD-L1 TPS scores translated to greater benefit with pembrolizumab (≥1%: HR, 0.81; 95% CI, 0.71-0.93; P = .0018; ≥20%: HR, 0.77; 95% CI, 0.64-0.92; P =.0020; ≥50%: HR, 0.69; 95% CI, 0.56-0.85; P =.0003).

“Patients with high TPS [should receive] single-agent immunotherapy; it’s my treatment of choice for them,” said Patel. “For patients who don't have high TPS, the combination of chemotherapy and immunotherapy has shown benefit across the board.”

In an interview during the 2019 &#8239;OncLive State of the Science Summit™ on Lung Cancer, &#8239;Patel discussed the implications of genetic testing, the lasting impact of the KEYNOTE and IMpower trials in patients with advanced nonsquamous NSCLC, and considerations for treatment selection.

OncLive: What does the current treatment paradigm look like for stage IV nonsquamous NSCLC?

Patel: We have seen stepwise improvements with multiple chemotherapy backbones and immunotherapeutics that have led to personalized therapy for patients without genotypic drivers.

NSCLC has undergone dramatic changes in the past several years. We have targeted therapy for patients with actionable alterations beyond well-established biomarkers, such as EGFR, ALK, and ROS1. We’ve seen emerging biomarkers, like MET and RET. However, the vast majority of patients don’t have a targetable alteration. Those patients are treated primarily with the combination of chemotherapy and immunotherapy, or immunotherapy alone. Our decision between immunotherapy [alone] versus the combination of chemotherapy and immunotherapy is based on disease biology, tumor markers, burden of disease, and patient preference.

Could you discuss the importance of doing genetic testing before starting immunotherapy?

It's absolutely essential to do genotyping so that we can identify drivers, such as EGFR, ALK, and ROS1. We have oral agents that are remarkably effective for those patients. Patients with an ALK translocation may be looking at several years on oral therapy; these therapies are associated with deep responses, tumor shrinkage, and are generally well tolerated.

Some retrospective studies have demonstrated that if a patient switches over to a TKI after receiving chemotherapy and immunotherapy up front, they will experience increased toxicity, which may lead to pneumonitis, colitis, and hepatitis.

How have the results of the KEYNOTE-189 and IMpower150 trials impacted standard of care?

For patients who don’t have an actionable target, we’ll assess for PD-L1. Patients who have a TPS >50% by immunohistochemistry should receive pembrolizumab alone. For the majority of patients who have PD-L1 TPS <50%, we generally recommend a combination of chemotherapy and immunotherapy. We have established pembrolizumab in combination with carboplatin and pemetrexed from KEYNOTE-189 as a gold standard. In the trial, we saw improved response rates, progression-free survival, and OS with the addition of pembrolizumab. Moreover, updated OS analyses have been presented and the data are quite favorable.

IMpower150 and IMpower130 were done in the same setting. In IMpower150, patients received carboplatin, paclitaxel, bevacizumab, and atezolizumab. There is scientific rationale for the combination of chemotherapy and immunotherapy. We believe that the combination increases neoantigen presentation and results in a more favorable immune environment. The addition of bevacizumab inhibits the VEGF pathway, which we believe improves dendritic cell function and leads to a synergistic benefit with the quadruplet therapy.

What would lead you to choose the quadruplet regimen over the triplet with pembrolizumab?

We believe that synergy exists between VEGF and PD-1 antibodies; however, the toxicities are significant. Patients with renal insufficiency who may not be eligible for pemetrexed, or those who may have had adjuvant pemetrexed [may be better suited to receive the quadruplet therapy with atezolizumab]. Additionally, [we could consider this regimen] in patients with EGFR or ALK mutations [who progressed on prior TKI therapy].

What other novel immunotherapy combinations are under investigation?

The CheckMate-227 trial has held our attention for years. We’ve seen multiple iterations of that trial. For example, at the 2019 ESMO Congress, we saw the comparison between the combination immunotherapy arm and the chemotherapy arm. The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) reached statistical significance in patients with PD-L1 TPS >1%. Even patients without PD-L1 expression seemed to benefit pretty substantially from the combination. These results are exciting for patients who may prefer a chemotherapy-free backbone. A pretty significant number of complete responses with the combination were observed, and toxicity was well managed. The question is, “How are we going to select patients for the double immunotherapy combination?”

Where do you see research heading in the next few years?

Several important questions need to be answered. Duration of therapy is still open-ended. For someone who had a terrific response and still has evaluable disease, is there a time that you should stop treatment? Studies have looked at a 2-year [duration], but it’s unclear what the optimal duration is. Also, is de-escalated treatment appropriate for patients who have deep responses?

The big question is, “How do we refine patient selection?” With genotyping, we can say with certitude that the patient is or isn’t going to respond to certain oral drugs. With immunotherapy, even if a patient has high PD-L1 expression, there’s a 50/50 chance of response. We need to improve our personalized treatments.

What is your take-home message to your colleagues on these advances?

Several changes have been adopted into clinical practice in recent years at a dizzying pace. One is that all newly diagnosed patients with nonsquamous NSCLC need genotyping. Getting the right answer up front gives us many opportunities for treatment. For example, with RET translocations, we’re seeing deep responses [with RET-targeted therapy]. Although we don't currently have an FDA-approved drug [for RET], we may soon.

With immunotherapy, we’ve seen dramatic and durable responses. Better prediction and assessment of which patients will respond to single-agent immunotherapy [will be important].

Lung cancer has become a chronic disease in many individuals. [Treatment is] more of a marathon than a sprint, so we have to be judicious with therapy and hold onto single-agent therapies, potentially re-challenge patients, and enroll patients on clinical trials to expose them to other innovative approaches down the road.

References

1. Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC.&#8239;J Clin Oncol.&#8239;2019;37(suppl 15; abstr 9013). doi: 10.1200/JCO.2019.37.15_suppl.9013.
2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.&#8239;N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.
3. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small cell lung cancer (KEYNOTE-042): a randomized, open-label, controlled, phase 3 trial.&#8239;Lancet. 2019;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7.