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Levy Works Through Therapy Options in Patients With NSCLC Who Lack a Driver Mutation

Audrey Sternberg
Published Online:6:27 PM, Thu April 18, 2019

Benjamin P. Levy, MD

During a Targeted Oncology live case-based peer perspectives presentation, Benjamin P. Levy, MD, recently discussed the treatment considerations and decisions he makes when treating patients with non–small cell lung cancer (NSCLC). Levy, the clinical director of medical oncology and associate professor of oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, revealed his treatment decisions to the group based on 2 case scenarios of patients with NSCLC that does not have a genetic driver.

Case 1

A 59-year-old Caucasian man presented with symptoms of chest pain, cough, and dyspnea. His past medical history was remarkable for hypertension, osteoarthritis, and former smoker with 10 pack-years.

CT imaging of the chest and abdomen revealed a 9.0-cm spiculated mass in the left lower lobe, loculated pleural effusion in the left hemithorax, diffuse liver nodules, and right adrenal metastases. Also, PET/CT scan showed fluorodeoxyglucose (18F-FDG) uptake in the left lung mass, pleura, liver, and right adrenal gland. A brain MRI indicated that the patient was negative for intracranial metastases.

Upon physical exam, decreased breath sounds were noted in the left lung base, but hepatomegaly was not observed. The patient had an ECOG performance status of 1.

Next-generation sequencing (NGS) was negative for molecular aberrations in EGFR, ROS1, BRAF, ALK, RET, MET, HER2, and KRAS. By immunohistochemistry (IHC), the PD-L1 expression level was found to be 10% and the tumor mutational burden (TMB) was 10 mutations/megabase.

Image-guided biopsy of the liver lesion showed a poorly differentiated adenocarcinoma of the lung.

What are your initial impressions of this patient?

This is a 59-year-old man who had the usual past medical history and presents as a former smoker, 10 pack-years, with a huge 9-cm mass in the left lower lobe; pleural effusion; liver nodules; PET scan uptake; negative MRI; and a physical exam that was unremarkable other than the decreased breath sounds on the left lung base. He presented with stage IV lung cancer, liver metastases, and a very large, vesiculated mass. Image-guided biopsy of the liver lesions showed poorly differentiated adenocarcinoma of the lung.

What would be your initial genomic workup on this patient based on this presentation?

I think that comprehensive genomic profiling is probably the way to go now in lung cancer. EGFR, ALK, ROS, and BRAF are the 4 [genes that are regularly tested for under the current standard of care, have FDA-approved tests,] and have a vetted targeted therapy. We have osimertinib [Tagrisso] for EGFR mutations, alectinib [Alecensa] for ALK, crizotinib [Xalkori] for ROS1, and combination dabrafenib [Tafinlar] and trametinib [Mekinist] for BRAF. The recommendations have expanded to include testing for RET, MET, HER2, and KRAS. The way things are moving in lung cancer is that [these tests] should be done all at once rather than sequentially. At Johns Hopkins Medicine, we do not do EGFR, ALK, ROS1, and BRAF and then, if those are negative, the rest. We do all at once.

We have [many] drugs moving down the pike that are targeting rare mutations. [In more rare mutations like RET,] treating patients with a drug like LOXO-292—which [may] soon be approved for RET rearrangements—and seeing the difference between what that does, compared with chemotherapy, may alter perceptions moving forward. We are in this transition period of trying to understand what to test for. The mandatory minimum is EGFR, ALK, ROS1, and BRAF, and the shift is toward considering MET exon 14, RET rearrangements, HER2, and KRAS.

Then, there are other mutations like NTRK fusions that make up <1% of all lung cancers. A New England Journal of Medicine article is about the use of larotrectinib [Vitrakvi] in a tissue-agnostic population that includes patients who are NTRK fusion–positive.1 It did not matter where the tissue came from. If there was an NTRK fusion underpinning, pediatric and adult patients responded to the drug, and that led to the larotrectinib approval.

The other thing you could do is a sequential [strategy by starting with] EGFR, ALK, and ROS1. If those are negative, you could retest for these others. The nice thing is that these mutations are mutually exclusive. If the patient has KRAS, they do not have EGFR, and if they have EGFR, they do not have RET.

Would you use the patient’s high TMB to target your treatment recommendation?

TMB in this patient was 10 mutations/megabase. Foundation Medicine’s assay, FoundationOne CDx, and Hopkins both test for it. Some interesting data may be coming out showing that TMB may help drive treatment decisions with dual-checkpoint blockade. I do not think we are there yet. I do not routinely look at TMB and I do not use it in how I drive treatment decisions [because] I think we need more work with TMB.

Testing for TMB needs a lot of tissue, and that is why it is the last test. If you look at the FoundationOne CDx report, often it will [indicate that TMB was not tested] because there was not enough tissue. We have had this issue at Hopkins as well, in which TMB testing requires more tissue. PD-L1 testing typically requires 1 slide whereas TMB typically requires 10 to 15 slides. If we need to use the tissue for prioritization of other things and I do not know what to do with a high-TMB patient, then what am I going to do with that information? It does not drive my treatment decision, so I think we have a lot more to learn with TMB.

What is the preferred recommendation for a patient who lacks a driver?

This patient was negative for actionable aberrations. Regardless of PD-L1 expression, I generally still use the triplet regimen of pembrolizumab [Keytruda], pemetrexed [Alimta], and either carboplatin or cisplatin. That is something that was seen in the KEYNOTE-189 trial [NCT02578680]. The trial included patients with <1% PD-L1 expression, and they did derive a meaningful benefit from therapy. I always talk about the negative predictive value of PD-L1. If the patient has low PD-L1 expression, we know that they still respond. It is not a perfect biomarker. Some patients who have negative PD-L1 expression still have a meaningful benefit with immunotherapy.

With KEYNOTE-189, you are basically giving everyone 3 drugs with no biomarker, and they showed a benefit. It was antithetical to the whole idea of precision medicine. Generally, we try to define the right subsets of patients and give the right drug, but in this study, we just gave it to everybody, and they did fine.

What would you do for the same patient who had >50% PD-L1 expression?

What we generally do is look at symptom burden. If they have a heavy burden and I have 1 shot at treatment, I will give them all 3 drugs. If they are more beat-up and I do not need to “decompress” them or systemically debulk them, then I will give them single-agent pembrolizumab. We have 2 indications there.

Are there other options that you could use in this patient?

The combination of carboplatin, paclitaxel, bevacizumab [Avastin], and atezolizumab [Tecentriq] is now approved in patients who are treatment-naïve and lack a driver mutation. These data were presented at the American Society of Clinical Oncology 2018 Annual Meeting and subsequently published in the New England Journal of Medicine.2 Similar to KEYNOTE-189, IMpower150 tested carboplatin, paclitaxel, and bevacizumab alone or in combination with atezolizumab. An immunotherapy drug is added to a platinum doublet and is compared with a platinum doublet alone in an unselect patient population and there is a benefit.

The approval just happened in December 2018. This is among the few trials that allowed EGFR and ALK patients who had received a tyrosine kinase inhibitor [TKI] prior to enrolling on the study. Typically, we do not think that immunotherapy works in patients with EGFR and ALK [mutations, but] in this trial the addition of atezolizumab to chemotherapy compared with chemotherapy alone in patients who already received a TKI showed an overall survival [OS] advantage.

Case 2

A 62-year-old man presented to his primary care physician complaining of persistent right-sided neck pain. Two months later, he developed decreased appetite, lethargy, and a dry cough. His past medical included hypercholesterolemia and arthritis. He was a former smoker but had no allergies and no family history of lung cancer.

An MRI of the neck revealed a spine lesion, and a chest CT showed a 4.3-cm right upper lung (RUL) mass with enlarged right hilar and right paratracheal lymph nodes. A PET scan indicated that there was 18F-FDG uptake in the RUL mass, the hilar and paratracheal nodes, and multiple cervical and thoracic vertebrae. A brain MRI was done and was negative for metastases.

A CT-guided biopsy of the RUL mass revealed adenocarcinoma that was positive for thyroid transcription factor-1. The patient was diagnosed with T2N2M1b metastatic lung cancer.

NGS testing was done and was negative for EGFR, ROS1, RET, BRAF, HER2, and NTRK, and IHC testing was negative for ALK gene rearrangements. PD-L1 expression was found in 0% of cells.

Notable laboratory findings included an elevated carcinoembryonic antigen (CEA) of 26 ng/mL; low albumin, 3.4 g/dL; normal creatinine levels; a normal complete blood count (CBC); and normal liver function.

The patient was started on pemetrexed, carboplatin, and pembrolizumab every 3 weeks, and on vitamin B/folic acid supplement.

Describe the difficulty in treating this patient.

This patient was driver-negative with a PD-L1 expression of 0%. The first-line option in this patient was the KEYNOTE-189 regimen, which is what I would probably start with. This patient started on carboplatin, pemetrexed, and pembrolizumab, and after 2 cycles the patient did not do well with the triplet regimen.

After 1 cycle of treatment with the triplet regimen, physical exam revealed that the patient had no palpable lymph nodes, decreased breath sounds in the RUL, and persistent symptoms. The patient had an ECOG performance status of 1. Laboratory findings indicated that his CEA level had increased to 28 ng/mL, and his CBC showed mild anemia in terms of a hemoglobin (Hb) of 11.0 gm/dL.

After cycle 2, imaging showed a progression in the RUL mass, which was now 5.2 cm, and several bone lesions. Laboratory findings indicated that his CEA level had risen again to 34 ng/mL and he had decreased albumin (3.2 g/dL) and further decreased Hb (10.2 gm/dL).

What is the preferred regimen for this patient after disease progression?

We are so excited that we moved pembrolizumab to the frontline. The problem is that there is a vacuum regarding what we do next. This patient progressed after 2 cycles and he was disappointed.

I think patients who have disease progression on frontline therapy need a therapeutic switch from the options reviewed. This patient received docetaxel plus ramucirumab. I would make the argument that this regimen was not tested in patients who had received the KEYNOTE-189 regimen, because it was not approved yet. This was used in patients who had received carboplatin plus pemetrexed, who were then randomized to docetaxel versus docetaxel plus ramucirumab, and there was an OS advantage of 1.4 months.3 I would argue that in lung cancer, any survival benefit is meaningful if you can modify or adjust the dosage to make sure the patient tolerates it.

The patient received docetaxel plus ramucirumab (Cyramza).

Which patients derive the greatest benefit from treatment with ramucirumab?

The investigators had also done an exploratory analysis that looked at patients who had rapidly progressed on induction chemotherapy.4 This was a second-line trial comparing docetaxel versus docetaxel plus ramucirumab. If you look at the subset of patients who did not do well with frontline chemotherapy, or those who progressed within 4, 8, or 12 weeks from the start of frontline chemotherapy and were not able to complete most cycles, docetaxel plus ramucirumab showed a meaningful benefit. Because of that, I think these are compelling data.

I would use docetaxel plus ramucirumab on patients who have progressed on the KEYNOTE-189 regimen. The problem with this regimen is not [with] the ramucirumab—it is with the docetaxel. I think we all know we have challenges with docetaxel. Interestingly, a subset of patients in the trial who received bevacizumab and added ramucirumab to docetaxel still derived a benefit. You would not think [they would], because they had already received an angiogenesis inhibitor. But when you gave them this regimen, they still derived a benefit.

What is happening now is that you do the trial, you see what is happening, and you go back and try to explain it from a preclinical side. I think they are still trying to work out why this is happening and why patients who should not derive a benefit do derive a benefit like this.
  1. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.
  2. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.
  3. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi: 10.1016/S0140-6736(14)60845-X.
  4. Reck M, Paz-Ares L, Bidoli P, et al. Outcomes in patients with aggressive or refractory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181-187. doi: 10.1016/j.lungcan.2017.07.038.

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