How EGFR and PD-1 Pathway Agents May Change Lung Cancer Care

Mark Socinski, MD

As new targeted and immunologic agents are introduced for patients with lung cancer, clinicians have more factors to consider than ever before when developing treatment plans for their patients. In an effort to help shed light on the latest research, leading experts in the field shared their thoughts on how the new data might influence current practices during a recent OncLive Peer Exchange program.

The panelists discussed data presented at the 2015 ASCO Annual Meeting including findings for small cell lung cancer (SCLC), which historically has had few therapeutic options.

EGFR-Targeting Therapies

Incorporating Gefitinib

“Modern treatment of advanced lung cancer is based on tumor histology and molecular subtype, with new advances in the field happening at an accelerated pace,” noted moderator Mark A. Socinski, MD, as he launched a wide-ranging discussion.With the approval of Iressa (gefitinib) in July, oncologists have one more epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in their armamentarium. In 2003, gefitinib became the first EGFR inhibitor approved for patients with non—small cell lung cancer (NSCLC), but the product was withdrawn after postmarketing studies failed to confirm a clinical benefit.

Since that time, data among patients with known mutation status have shown there is a benefit in EGFR-positive disease. The latest approval is for first line use in patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations.

Mary Jo Fidler, MD

One interesting point about the phase IV data from the IRESSA Follow Up Measure (IFUM) study,¹ noted Mary Jo Fidler, MD, is the use of serum samples in mutation testing. At baseline, one tissue and two plasma samples were collected for EGFR mutation analysis. A comparison of baseline tumor and plasma EGFR mutation status was part of the preplanned analyses. The results showed a high concordance (94.3%) between samples.¹

“Though tissue certainly is more sensitive, the trial showed that you can, in fact, detect the EGFR gene activating mutation in serum, which I thought was pretty exciting,” remarked Fidler.

The panel discussed how they would incorporate gefitinib into treatment regimens, given the availability of two other EGFR inhibitors, erlotinib and afatinib, for treatment in this population. Roy S. Herbst, MD, PhD, noted that there are many similarities between erlotinib and gefitinib.

However, one of the differentiating factors is the dosing. With erlotinib, the recommended starting dose is 150 mg, and that is usually reduced. By contrast, gefitinib is given as a fixed dose at 250 mg.

Roy Herbst, MD

Third-Generation Inhibitors

Geoffrey R. Oxnard, MD, echoed this assessment, noting that the fixed dose could be seen as an advantage. “Some [physicians] like gefitinib because it’s flat dosing. You don’t have to dose adjust,” said Oxnard. He added that, although erlotinib offers flexibility with dosing, “it’s a little more work to find the right dose for the patient.”The panel discussion turned to the topic of acquired resistance, a common occurrence in patients treated with targeted agents that presents significant treatment challenges.

There are promising new data in patients whose tumors develop the EGFR T790M mutation, the dominant mutation pattern observed in EGFR-positive NSCLC.

Third generation TKIs, rociletinib (CO-1686) and osimertinib (AZD9291), target sensitizing mutations, but do not target wild-type EGFR. Thus, there is less rash and diarrhea associated with these agents compared with first- and second- generation drugs that have greater potency toward wild-type EGFR, noted Oxnard.

It is unclear, however, whether current assays are accurately detecting the T790M mutation. Oxnard commented that he sometimes finds the mutation in serum samples or a rebiopsy after not finding it in an initial tissue biopsy. “There does have to be some persistence to find it, so it’s a little bit of a moving target,” said Oxnard. “But there are some patients who don’t benefit, and we want to find those people, too.”

A study presented at 2015 ASCO compared the efficacy of rociletinib in plasma-genotyped versus tissue-genotyped T790M-positive NSCLC.² The RECIST objective response rate (ORR) was approximately 48% in T790M-positive patients, regardless of the method used.² Liquid biopsies, added Oxnard, are less reliable in patients who have slow-growing disease because there is less DNA circulating in the blood in earlier stages. Patients whose tumors are T790M-negative in both the tissue and serum samples most likely have a different resistance mechanism, he said.

Geoffrey R. Oxnard, MD

New data presented at 2015 ASCO in 60 patients with EGFR mutation-positive advanced NSCLC showed efficacy and safety with osimertinib first-line.³ The study found that osimertinib was associated with an ORR of 70% (60% at the 80-mg dose, 80% at the 160-mg dose).³ Oxnard commented that the findings demonstrate that osimertinib “is actually not just a T790M inhibitor, but is a great EGFR inhibitor with a different toxicity profile and less of the rash and diarrhea.”

The jury is still out regarding whether the third-generation agents can ultimately replace the current standards of care, noted Naiyer Rizvi, MD. However, the data do suggest the newer agents have a better toxicity profile. “I think certainly from a tolerability standpoint and quality of life standpoint, the next-generation compounds are much better tolerated,” said Rizvi.

EGFR Inhibitors in Squamous Cell Carcinoma

“I think the patients that we treat with first-generation [agents]—not just the diarrhea, but the skin toxicity, the nail changes, and the fatigue really affect quality of life.”The anti-EGFR TKIs afatinib and erlotinib have also shown activity in patients who have squamous cell carcinoma. These patients are predominantly EGFR wild-type. A study in the second-line setting comparing these agents was presented at 2015 ASCO. The LUX-Lung 8 study found improved overall survival (OS) of 7.9 months versus 6.8 months (P = .008) and improved progression-free survival (PFS) of 2.6 months versus 1.9 months (P = .010) with afatinib versus erlotinib, respectively.⁴

Fidler commented that patients who are EGFR wild-type sometimes benefit from first-generation TKIs. However, it is difficult to determine who will benefit, and the PFS data are not overly high. Herbst stated that, although he does not often use TKIs in squamous cell carcinomas, he found the data from LUX-Lung 8 compelling. “I think the clinical trial showed a benefit, and there are very limited options in the squamous cell space,” said Herbst.

“We have our Lung-MAP trial where we’re looking for new targets, but even with that it’s hard to find genetic-driven targets in that setting.”

Panelists mentioned another anti-EGFR therapy in development for squamous cell NSCLC. Necitumumab is pending approval as a first-line treatment for locally advanced or metastatic squamous cell NSCLC.

Immunotherapy in NSCLC and SCLC

NSCLC

The pivotal study, SQUIRE, showed a 1.6-month improvement in median OS when necitumumab was added to gemcitabine and cisplatin compared with the gemcitabine-cisplatin regimen alone.⁵ The benefit seen in SQUIRE was modest, remarked Herbst. However, the data should be viewed in the context that the trial was conducted among patients with squamous cell disease and that the agent was evaluated against gemcitabine and cisplatin. A biomarker is needed to help determine those with squamous cell histology who are most likely to benefit, noted Herbst.Immunotherapy agents that target the PD-1/PD-L1 pathway have consistently demonstrated activity in about 20% of patients, noted Rizvi. Data presented at 2015 ASCO demonstrate a survival benefit with the PD-1 inhibitor nivolumab versus docetaxel in both squamous and nonsquamous NSCLC.^6,7

In the phase III CheckMate-017 trial,⁶ there was a 41% reduction in the risk of death with nivolumab versus docetaxel in the squamous setting. In the phase III CheckMate-057 trial,⁷ the reduction in risk of death with nivolumab was 27% in patients with nonsquamous NSCLC. Both studies enrolled patients who had progressed after platinum-based doublet chemotherapy.

Herbst commented that it is important to identify upfront those who are likely to benefit from immunotherapy.

“It does look like there are many who are not benefiting as well, and if we could figure out who those [patients] are, they might need to get combinations of therapies and other sorts of cocktails,” said Herbst. There are other compounds that block the PD-1 pathway that have shown promise, said Rizvi.

“PD-L1 is what’s expressed by tumor cells,” he said. “The PD-1 agents such as pembrolizumab and nivolumab bind to the T-cell side, whereas durvalumab and atezolizumab bind to the PD-L1 side.”

Naiyer Rizvi, MD

Because PD-L1 binds to PD-1, measuring PD-L1 on a tumor should predict response with PD-1 inhibition, Herbst noted. However, data are mixed regarding the utility of PD-L1 as a predictive biomarker. The heterogeneity of the tumor and changing expression levels over time add to the complexity, he added.

Another analysis presented at 2015 ASCO involved data from KEYNOTE-001, which examined the use of pembrolizumab as first-line therapy in patients with PD-L1-positive metastatic NSCLC. The recent analysis, led by Rizvi, explored the correlation between PD-L1 expression levels and efficacy in KEYNOTE-001.⁸ The results showed that the greatest efficacy was in patients with PD-L1 staining in more than 50% of tumor cells.⁸

Rizvi explained that the study looked only at nonsynonymous mutations, which alter the amino acid sequence of the protein. “If you did just the whole exome and just all of the mutations, it didn’t really matter,” stated Rizvi. “But if you looked at nonsynonymous mutations—the ones where the protein was changed—we found a highly significant difference in terms of those more mutated tumors responding much better than those that were less mutated.”

Frontline use of immunotherapy would be highly beneficial in certain patients, said Herbst. It is unclear whether chemotherapy should be used along with immunotherapy. Rizvi agreed that more data are needed in first-line use of these agents. First-line chemotherapy could be harming the T-cells before the immuno-oncology drugs are given, hampering their true effect.

SCLC

Immunotherapies are not without toxicities, cautioned Rizvi. It is important to be vigilant about liver enzymes, gastrointestinal toxicities, and the thyroid and adrenal axis. In addition, it is critical to treat patients who develop serious toxicities aggressively and quickly, he said.Data in SCLC demonstrated a benefit with combination immunotherapy, noted Rizvi. The addition of the PD-1 inhibitor nivolumab to the CTLA-4 inhibitor ipilimumab was found to improve response versus nivolumab alone in patients with SCLC who were platinum sensitive or refractory and had progressive disease, regardless of PD-L1 expression.⁹ Rizvi commented that patients who are PD-L1—negative may be the ones who benefit most from CTLA-4 inhibition.

A separate study in patients with SCLC that progressed on platinum-based chemotherapy showed a benefit with pembrolizumab in PD-L1—positive disease.¹⁰ The data from both of these studies are impressive, given the “huge abyss of options” in relapsed SCLC, noted Socinski.

Herbst agreed, noting there are other ongoing studies with immunotherapy in SCLC. “I think that’s great because that’s clearly an area where there hasn’t been anything new in quite some time with many failed trials,” said Herbst.

The trials thus far point to a need to drive immune activation harder in SCLC than in NSCLC, noted Rizvi. This could explain why the combination works better than monotherapy. “There’s clearly some other immunosuppression that’s going on in small cell which is completely different than non—small cell… I think that it shows that all these tumors are not the same and you need to think about them a little differently,” he said.

Clinical trial data and experience in the community setting will help oncologists optimize the use of these new immuno-oncology agents, Herbst said. “It’s just the tip of the iceberg because there are so many other immune inhibitors which we probably don’t have time to talk about, but it’s an exciting field and the science is going to drive things. Clinical trials and clinical trials with biopsies will really help us to figure out what’s next.”

References

1. Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study [published online November 21, 2013]. Br J Cancer. 2014;110(1):55-62.
2. Sequist LV, Goldman JW, Wakelee HA, et al. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts). J Clin Oncol. 2015;33(suppl;abstr 8001).
3. Ramalingam SS, Chih-Hsin Yang J, Lee CK. AZD9291, a mutant-selective EGFR inhibitor, as first-line treatment for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): results from a phase 1 expansion cohort. J Clin Oncol. 2015;33(suppl; abstr 8000).
4. Soria JC, Felip E, Cobo M, et al. Afatinib (A) vs erlotinib (E) as second-line therapy of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following platinum-based chemotherapy: overall survival (OS) analysis from the global phase III trial LUX-Lung 8 (LL8). J Clin Oncol. 2015;33(suppl; abstr 8002).
5. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial [published online June 1, 2015]. Lancet Oncol. 2015;(16)7:763-774.
6. Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr 8009).
7. Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr LBA109).
8. Rizvi NA, Garon EB, Leighl N, et al. Optimizing PD-L1 as a biomarker of response with pembrolizumab (pembro; MK-3475) as first-line therapy for PD-L1—positive metastatic non-small cell lung cancer (NSCLC): updated data from KEYNOTE-001. J Clin Oncol. 2015;33 (suppl;abstr 8026).
9. Antonia SJ, Bendell JC, Taylor MH, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol. 2015;33(suppl;abstr 7503).
10. Ott PA, Fernandez ME, Hiret S, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): preliminary safety and efficacy results from KEYNOTE-028. J Clin Oncol. 2015;33(suppl; abstr 7502).