Shares of Nektar Therapeutics [NKTR] declined about 40% on June 2 after reporting preliminary data from a phase I/II PIVOT-02 trial in cancer patients.
Nektar tested its drug NKTR-214 and Bristol-Myers Squibb’s Opdivo (nivolumab) as a combination therapy in five types of cancer in the PIVOT-02 trial. The phase I/II trial had multiple objectives but a key result sought by Nektar and Bristol-Myers was how NKTR-214 boosted the effectiveness of Opdivo across the treatment of different cancers.
Investors legitimately responded on the efficacy results of the PIVOT-02 trial, noting the overall response rate (ORR) declined sharply in melanoma and renal cell carcinoma (RCC) patients. Phase I/II trials, however, typically are used to determine dose escalation levels and to refine how a new therapy works. PIVOT-02 is no different, explaining why Nektar stressed a key finding from PIVOT-02 was the ability of NKTR-214 to stimulate PD-1 expression in PD-L1 negative patients.
The higher expression of PD-1, the more effective Opdivo becomes, which was the purpose of Bristol-Myers’ $1.85 billion cash investment in NKTR-214 four months ago. The increase of PD-1 expression may prove more valuable to NKTR-214 than a preliminary affirmation of the efficacy in a second group of patients.
In PIVOT-02, the data presented by Nektar demonstrated conversion of PD-L1 negative status at baseline to PD-L1 positive status at week three in 9 of 17 patients, or 53%. Of these previously PD-L1 negative patients, 78% achieved clinical benefit as defined by stable disease, partial response or complete response.
The finding will help the partners recruit additional patients appropriate for PIVOT- 02, which is being tested in more than 400 patients with melanoma, renal cell, urothelial, non-small cell lung and triple negative breast cancers. The PIVOT-02 data on June 2 cited efficacy results from approximately 75 Stage 4 cancer patients with melanoma, RCC and urothelial cancers.
Digging deeper into the efficacy, the overall response rate (ORR) in melanoma fell to 50% from 84.6% between the stage 1 and stage 2 parts of the trial. In RCC, the ORR declined to 46.2% from 63.6%. However, differences between the stage 1 and stage 2 portions of the trials that should be noted.
For example, the stage 2 portion of the melanoma indication included twice as many patients. Considering how small the patient pool was in the stage 1 portion (only 13 patients), it was unlikely the 84.6% response rate would be maintained in a larger data set (28 patients). The median time for the assessment was only 4.6 months, which is an extremely brief period to determine which patients are responders and non-responders. Moreover, all the patients evaluated were considered Stage 4 –the most advanced stage of cancer, in which a patient’s immune system has been severely compromised.
Melanoma and RCC are large markets in which the partners want to thrive but the urothelial cancer efficacy results should not be overlooked. In urothelial cancer, the ORR was 60% (six of 10 patients) after a median period of 3.9 months, which met the threshold for additional enrollment. The 60% ORR applied to both PD-L1 positive and PD-L1 negative patients.