Expert Reflects on Recent Advances in Lung Cancer

Kaushal Parikh, MD, MBBS

The treatment landscape of lung cancer has expanded to include more novel agents and combination strategies, said Kaushal Parikh, MD, MBBS, adding that the approaches include both immunotherapies and targeted agents.

Practice-changing data were shared at several recent conferences, including the 2019 ASCO Annual Meeting, 2019 ESMO Congress, and 2019 World Congress on Lung Cancer. For example, updated findings from the phase III FLAURA trial presented at ESMO demonstrated a 20% reduction in the risk of death with osimertinib (Tagrisso) compared with erlotinib (Tarceva) or gefitinib (Iressa) in patients with EGFR-mutant, advanced non—small cell lung cancer (NSCLC; HR, 0.799; 95% CI, 0.647-0.997; P = .0462).

Despite advances such as this one, biomarker identification is critical to push this field forward and allow the optimal utilization of available agents, said Parikh.

"It is important to learn which patients will benefit with which drugs. Up until now, we have seen a 30% to 35% response rate with immune checkpoint inhibitors," said Parikh. "We need better biomarkers to predict survival benefit."

In an interview with OncLive^®, Parikh, a medical oncologist in the Division of Thoracic Oncology and Early Therapeutics at Hackensack University Medical Center, reflected on pivotal lung cancer data shared at recent major oncology meetings.

OncLive: It has been a significant year for lung cancer. Reflecting on the 2019 ESMO Congress, what immunotherapy data stood out to you?

Parikh: It's really been an exciting 5 years in lung cancer. From the 2019 ESMO Congress, the 2 immunotherapy trials that stood out were CheckMate-227 and IMpower110. CheckMate-227 was a large, complicated trial of 1700 patients. [In part 1a], these patients were randomized 1:1:1 to receive nivolumab (Opdivo) plus ipilimumab (Yervoy), chemotherapy, or nivolumab alone. At the 2019 ESMO Congress, the OS data of the combination were presented for patients who had PD-L1 expression ≥1%.

We saw a positive overall survival (OS) signal from the combination, with a median OS of 17.1 months versus 14.9 months with chemotherapy in the PD-L1—positive patients. There was also a clinically significant survival benefit seen in all-comers, including PD-L1–negative patients.

This combination gives us another option for our patients in the frontline setting. We do need to be aware of the toxicity profiles of these 2 drugs given concurrently for a patient with a high PD-L1 status. We have been using pembrolizumab (Keytruda) for a few years now, and it does appear to be a safe option. However, in several patients, nivolumab/ipilimumab is an option.

The IMpower110 study looked at atezolizumab (Tecentriq) versus chemotherapy. Again, this was a large, randomized trial of 500 patients; however, only PD-L1—positive patients were included in this study.

Atezolizumab [has a companion] diagnostic PD-L1 assay, called the [VENTANA PD-L1 (SP142)], assay rather than the standard [PD-L1 IHC 22C3 pharmDx] assay, which is most widely used. The SP142 assay essentially gives us a PD-L1 expression on the tumor cell and immune cell as 1+, 2+, or 3+. The trial had a complicated, hierarchical statistical design. These patients needed to show a positive signal in the 3+ group, then show positive signals in the 2+ and 3+ groups, then show positive signals in the 1+, 2+, and 3+ groups for it to be actually analyzed for progression-free survival (PFS). This trial included all patients who had 1+ or above PD-L1 expression on the tumor cell or immune cell, with the primary endpoint being OS.

There was an OS advantage seen in the tumor or immune cells with 3+ PD-L1 expression. The median OS was about 20 months with single-agent atezolizumab versus 13 months with standard platinum-doublet chemotherapy. This benefit was seen regardless of histology, and was seen in both squamous and nonsquamous patients.

The only statistically positive finding we saw was in the 3+ population. We saw meaningful numbers for the remainder of patients, but it was not statistically significant.

What promising data have been shown with targeted therapies in lung cancer?

We saw some exciting data at the 2019 ESMO Congress, and prior to that meeting, regarding targeted therapies. At the 2019 ESMO Congress, we finally saw the OS analysis of osimertinib from the FLAURA trial, which has become our frontline treatment for EGFR-mutant lung cancers. We saw that osimertinib, compared with the first-generation TKIs gefitinib or erlotinib, had almost a 7-month OS advantage. Median OS was 38.6 months with osimertinib and 31.8 months for the earlier TKIs.

Other interesting TKIs are targeted therapies that are exciting are selpercatinib (LOXO-292) [from] the LIBRETTO-001 study, [which is looking at] RET fusion—positive NSCLC.

These treatment-naïve patients had an overall response rate of about 85% with central nervous system (CNS) activity. That’s encouraging for the 2% of patients with RET fusion—positive NSCLC.

Another drug for the same RET fusion—positive disease is BLU-667 [which was looked at in the ARROW study]. A good response rate of about 60% in prior platinum-treated patients [was noted with this agent].

Another exciting class of drugs in the targeted therapy spectrum are the KRAS G12C inhibitors. Clearly, this is the holy grail of oncology so far. G12C is present in about one-third of all KRAS-mutated patients. KRAS by itself is seen in about one-third of all patients with NSCLC. Therefore, about 10% of patients are eligible for AMG 510 and MRTX849. Both have shown good and durable responses. More importantly, they were both tolerable in phase I studies.

Could you discuss the early data we have seen with AMG 510 and MRTX849?

Both of these drugs have a similar efficacy profile; response rates are between 50% and 60% and are very well tolerated. AMG 510 is a once-daily regimen versus MRTX849, which is a twice- daily regimen.

A recent preclinical study showed that these drugs, especially AMG 510, may potentate immune response. We have evidence to show that immune-competent mice treated with AMG 510 have some immune signals as well.

In combination with checkpoint inhibitors, [the mice] can be cured so to say, or have very durable responses. This provides us with another platform to further these drugs and combine them with immunotherapy.

Theoretically speaking, patients who have other exposures, [such as a smoking history], tend to have [a higher frequency of] KRAS mutations. It would make sense, from a clinical perspective, to combine these TKIs with immunotherapy; however, we do not know about safety yet. There is some evidence of [more adverse events than normal] of TKIs combined with immunotherapy.

What will the OS data with osimertinib tell us? What do we do for patients who progress on osimertinib?

The key takeaway points on the FLAURA trial are that about 30% of patients did not end up receiving a second-line regimen in both arms. This makes a case for us to use our best drugs upfront. Right now, that is osimertinib.

Also, we have no way to predict which of the 47% of patients who received gefitinib or erlotinib and went on to receive osimertinib will develop T790M, [to know if they can] receive osimertinib after progression on the first-generation TKIs.

Lastly, osimertinib has CNS activity and is a safer option. These factors solidify osimertinib’s position as the standard of care for these patients.

At the 2019 ESMO Congress, another randomized phase III study was the RELAY trial, which looked at erlotinib with ramucirumab (Cyramza) versus erlotinib alone in the EGFR-mutated lung cancers. We saw an improvement in PFS with the combination of ramucirumab and erlotinib. These results show that osimertinib can be combined with bevacizumab (Avastin), [which is being tested] in ongoing clinical trials.

From the 2019 ASCO Annual Meeting, there was a study from India, which showed the combination of gefitinib with platinum-based chemotherapy in patients with EGFR-mutated lung cancer. That also had a significant OS advantage and a good safety profile.

We know that osimertinib is a very well-tolerated drug. This also presents the opportunity to further explore whether the combination of osimertinib with chemotherapy is advantageous, efficacious, and safe.

What are your thoughts on the POSEIDON data? How could those findings impact the landscape?

Thus far, we only have a press release showing that the POSEIDON trial reached its primary endpoint and the combination of durvalumab (Imfinzi) and tremelimumab, along with chemotherapy, showed a significant survival advantage.

Before we see these data, the concerns for this regimen are regarding toxicity. We know that combining CTLA-4 inhibition and PD-1/PD-L1 inhibition is generally more toxic than PD-L1 alone. This combination plus chemotherapy should make a physician concerned about potential toxicity, especially for those patients who may have poor-performance status or other comorbidities.

Is it possible to sequence these combinations of immunotherapy and chemotherapy?

It is important to identify which patients are going to benefit [from these combinations]. In terms of sequencing, somebody who has received a doublet of immunotherapy may go on to receive chemotherapy in the future. Somebody who have received chemotherapy upfront with pembrolizumab may receive another immunotherapy combination. [Those data] remain to be seen.

Most of our energy is dedicated toward overcoming resistance to immunotherapy. About 30% of these patients respond to immunotherapy, so there are some patients who are inherently resistant to immunotherapy. Some respond and then become resistant. There are several ongoing trials looking at overcoming the resistance to these drugs.

There are drugs targeting other checkpoints such as LAG3, TIM3, or OX40, the tumor microenvironment such as TGF-ß1, bispecific antibodies, and KRAS-targeted vaccines looking at potentiating the immune response. This is where our energy should be focused going forward.

Are there other trials you are eagerly awaiting the results of?

The immunotherapy drugs were initially approved for the advanced setting. Then, they moved to the second-line setting. Now, finally, they are being introduced to the frontline space.

Durvalumab has broken the frontline barrier, and is now approved for patients with stage III NSCLC following concurrent chemoradiation.

There are other trials looking at immunotherapies, as well as targeted therapies, in the adjuvant and neoadjuvant settings, and after chemoradiation. Osimertinib is being looking at in stage III EGFR-mutated NSCLC after concurrent chemoradiation.

The ALCHEMIST [trial is seeking] biomarkers for specific treatments in the adjuvant setting. I am excited about these and hopefully they will show good news for our patients.

Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Ffnal overall survival analysis. Presented at: 2019 ESMO Congress; September 28-October 1, 2019; Barcelona, Spain. Abstract LBA5_PR.