With more than a dozen treatments and products for lung cancer receiving FDA approval in 2018, clinicians have a new array of novel agents and regimens that hold great promise for patients to add to their armamentarium. To learn more, Healio spoke with Justin Gainor, MD, attending physician in the Center for Thoracic Cancers and director of Targeted Immunotherapy in the Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center, and assistant professor at Harvard Medical School, about the most practice-changing highlights in lung cancer in 2018 and what he hopes to see in the new year.
Justin Gainor, MD
In the targeted therapy sphere, there have been three noteworthy approvals over the last year. The first was the approval of osimertinib (Tagrisso, AstraZeneca), an EGFR inhibitor for first-line therapy. That approval was based on the FLAURA study, which randomized patients to either osimertinib or first-generation EGFR inhibitors. Osimertinib improved PFS significantly in that study. It has since become our standard-of-care for newly diagnosed, EGFR-positive patients.
Lorlatinib (Lorbrena, Pfizer), a third-generation ALK inhibitor, also received regulatory approval. This agent was approved for ALK-positive NSCLC patients with disease progression after crizotinib and at least one other ALK inhibitor. Thus, lorlatinib will become an important tool in the armamentarium for ALK-positive patients progressing on first- and second-generation ALK inhibitors. Remarkably, we now have five approved ALK inhibitors for ALK-positive non-small cell lung cancer.
The third targeted therapy approval worth mentioning is larotrectinib (Vitrakvi, Loxo Oncology), a TRK inhibitor. This approval represents a paradigm shift in that we now have a targeted therapy that was approved in a tumor agnostic fashion. It was approved for any solid tumor that has an NTRK rearrangement. This speaks to where the field may be moving as we start looking at alterations that are targeting increasingly smaller patient populations.
In the immunotherapy sphere, the biggest advance has been with chemotherapy plus PD-1 or PD-L1 combinations. We have now seen multiple clinical trials showing that the addition of PD-1/PD-L1 inhibitors to chemotherapy results in improvements in OS in both squamous and non-squamous histology. Certainly, chemotherapy plus PD-1 combinations will be the novel regimens that affect the largest number of patients. Those regimens include pembrolizumab (Keytruda, Merck) plus platinum-pemetrexed (Alimta, Eli Lilly and Company) and atezolizumab plus carboplatin, paclitaxel, and bevacizumab for patients with non-squamous histology, and pembrolizumab plus carboplatin and either paclitaxel or nab-paclitaxel in squamous cancers.
As soon as I saw the data for chemotherapy plus PD-1 combinations at AACR and ASCO, my impression was that these combinations should be the new standard of care, and so I adopted them quite quickly. The relevant trials are KEYNOTE-189 and IMpower150 in the case of non-squamous histology and KEYNOTE-407 in the case of squamous cancer. I think clinicians will feel comfortable with these regimens because they are already accustomed to using chemotherapy and have been using PD-1 inhibitors in lung cancer for several years now. It was a natural leap to the combination.
In terms of the targeted therapies, osimertinib is an agent that was previously approved for patients with a T790M resistance mutation, so clinicians already have some exposure to using the drug. This more recent approval moved it to the first-line space. In contrast, lorlatinib and larotrectinib are new agents that have not been previously approved. They are targeting molecular subsets that are smaller, and so clinicians may not see a patient with an NTRK rearrangement for some time. Implementation is going to require getting up-to-date with these newer agents and their toxicity profiles.
The partial clinical hold on tazemetostat (Epizyme) was placed due to a safety report of a pediatric patient who was enrolled in a tazemetostat trial who developed a secondary lymphoma. The hold was subsequently lifted after Epizyme submitted an assessment of the risk for secondary malignancies across all the company’s clinical trials. I think that this is just another example of when we introduce novel therapies into the clinic, we have to be open-minded about the potential for toxicity, including the emergence of new malignancies, to make sure we have the necessary precautions in place, as it seems like had been done here.
It is difficult to know exactly when approvals may be filed; however, there are promising areas that we hope will someday gain regulatory approval.
In the targeted therapy realm, we have seen some promising data targeting additional molecular subsets of patients, most notably patients with RET rearrangements and those with MET exon 14 skipping. With respect to RET, these rearrangements are seen in 1% to 2% of NSCLC cases. Over the last year, we have now seen the emergence of two selective RET inhibitors: LOXO-292 (Loxo Oncology) and BLU-667 (Blueprint Medicines). These inhibitors have shown very promising activity in RET fusion-positive lung cancer. LOXO-292 has gained breakthrough therapy status by the FDA. With respect to MET exon 14 skipping, a number of different MET inhibitors are in the clinic and have also shown exciting response rates in that molecularly-defined patient population.
In the immunotherapy realm, we have seen data with immunotherapy-immunotherapy combinations, such as PD-1 plus CTLA-4. In CheckMate-227, nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) produced significant improvements in PFS among patients with previously untreated lung cancer and a high tumor mutation burden. That regimen is currently being reviewed by the FDA.
One key development is the success of PD-1 inhibitors in patients with small cell lung cancer. One agent, nivolumab, was approved in the management of small cell lung cancer in the third-line space. In addition, we saw randomized phase 3 data evaluating the combination of atezolizumab (Tecentriq, Genentech), a PD-L1 inhibitor, plus standard first-line chemotherapy for small cell lung cancer. In that randomized phase 3 study of standard first-line chemotherapy plus or minus atezolizumab, patients who received atezolizumab had significant improvements in PFS as well as OS. That is one of the first significant modifications to our initial therapy for small cell lung cancer in decades, so it is an extremely exciting finding.
Another key development has been the movement of cancer immunotherapies into earlier stages of treatment. This really began with durvalumab (AstraZeneca), a PD-L1 inhibitor, showing an improvement in PFS among patients completing definitive chemotherapy and radiation for locally advanced NSCLC. In late 2018, we saw the OS results from that study, which were also positive. That is a major advance in the management of locally-advanced disease, and I think it opens us up to start exploring these agents in earlier stages of the disease. There are several ongoing studies looking into that very question.
Despite all the progress that has been made, we still have a lot to do in treating lung cancer. A critical need moving forward is for patients who are resistant or refractory to PD-1 pathway blockade. We have an urgent need for new therapies in that space. Much of the focus right now has been placed on developing novel combinations, generally with PD-1 inhibitors as a backbone Investigators are taking a variety of different approaches trying to overcome resistance, ranging from vaccine strategies to additional checkpoint inhibitors, as well as other ways to modulate the host immune system to enable it to recognize and eradicate tumors. That will be the greatest challenge over the next couple of years.
Disclosure: Gainor has served as a consultant or received honoraria from Agios, Amgen, Ariad/Takeda, Array, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Incyte, Jounce, Loxo, Merck, Novartis, Oncorus, Pfizer and Regeneron. He also has received research support from Ariad/Takeda, Genentech and Novartis.
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